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ROYAL COLLEGE OF PHYSICIANS
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Copyright 2008 Royal College of Physicians of London
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Contents
Guideline Development Group members
Preface
Acronyms, abbreviations and glossary
v
ix
x
Introduction
Background
Definition
Burden of disease
3
4
5
Methodology
Aim
Scope
Audience
Involvement of people with CKD
Guideline limitations
Other work relevant to the guideline
Background
The process of guideline development
Disclaimer
Funding
9
9
9
9
10
10
10
11
15
15
17
19
THE GUIDELINE
4
4.1
4.2
4.3
4.4
4.5
5
5.1
5.2
6
6.1
6.2
Investigation of CKD
Measurement of kidney function
Factors affecting the biological and analytical variability of GFR estimated
from measurement of serum creatinine
Detection of blood and protein in the urine
Urinary albumin:creatinine and protein:creatinine ratios, and their relationship
to 24-hour urinary protein
Indications for renal ultrasound in the evaluation of CKD
Classification and early identification
The influence of GFR, age, gender, ethnicity and proteinuria on patient
outcomes
Who should be tested for CKD?
Defining progression of CKD and the risk factors associated with
progression
Defining progression
Risk factors associated with progression of CKD
25
30
33
41
47
51
59
73
78
iii
7
7.1
Referral criteria
Indications for referral to specialist care
87
8
8.1
8.2
Self management
Modification of lifestyle
Dietary intervention and renal outcomes
89
95
9
9.1
9.2
9.3
9.4
9.5
123
126
129
10
10.1
10.2
10.3
133
135
139
11
11.1
Asymptomatic hyperuricaemia
Asymptomatic hyperuricaemia in people with CKD
145
12
12.1
147
13
13.1
13.3
14
14.1
15
15.1
15.2
Information needs
Information, education and support for people with CKD and their carers
Available tools to aid identification and maximise effectiveness of treatment
and management of CKD
177
182
REFERENCES
187
13.2
iv
101
111
http://www.rcplondon.ac.uk/pubs/brochure.aspx?e=257
Evidence-based clinical questions and literature searches
Scope of the guideline
Health economic model Cost effectiveness of CKD case finding among
people at high risk
GDG members declaration of interests
149
155
160
175
The following were invited to attend specific meetings and to advise the GDG:
Dr Claire Beeson acted as a deputy for Dr Shelagh ORiordan at a GDG meeting.
Dr Indranil Dasgupta, Consultant Nephrologist, invited to contribute at a specific meeting as
an expert representing the Type 2 Diabetes Guideline but was not a full member of the GDG.
Dr Patrick Fitzgerald acted as a deputy for Dr Ivan Benett at a GDG meeting.
Dr Neil Iggo, Consultant Nephrologist, acted as a deputy for Dr Lawrence Goldberg at a GDG
meeting.
Dr Kanchana Imrapur acted as a deputy for Dr David Stephens at a GDG meeting.
Dr Marta Lapsley acted as a deputy for Dr Edmund Lamb at a GDG meeting.
Ms Nicola Thomas acted as a deputy for Ms Natasha McIntyre at a GDG meeting.
vi
Acknowledgements
Acknowledgements
The Guideline Development Group is grateful to the following people for their valuable
contributions to the development of this guideline:
G
Dr Bernard Higgins, Director, NCC-CC
G
Ms Jane Ingham, Assistant Director, NCC-CC
G
Ms Susan Tann, Centre Co-ordinator, NCC-CC
G
Ms Jill Parnham, Associate Director, NCC-CC
G
Ms Diane Green, Dietician
G
Mr Rob Grant, Senior Technical Advisor, NCC-CC
G
Ms Claire Turner, Senior Project Manager, NCC-CC
G
Ms Taryn Krause, Project Manager, NCC-CC
Thanks also to the following NCC-CC research fellows: Anu Garrib, Rachel OMahony,
Jose Diaz, Roberta Richey and Sharon Swain.
vii
Preface
Chronic kidney disease (CKD) is of growing importance in the UK. The NHS is increasingly
focussing on prevention and on the early detection and treatment of potentially progressive
disease, whilst the prevalence of risk factors for CKD, such as diabetes, obesity and hypertension
is rising. It is therefore a great pleasure to introduce this timely new guideline on CKD from the
National Collaborating Centre for Chronic Conditions (NCC-CC) and the National Institute
for Health and Clinical Excellence (NICE).
The recommendations you will read here are the result of a thorough review of the published
research. The field of renal medicine has a complex evidence base, and enormous thanks are
due to the Guideline Development Group for their hard work and attention to detail, and to the
NCC-CC Technical Team who worked enthusiastically alongside them. As for all our guidelines,
full evidence tables summarising the clinical evidence base, and full details of the health
economic modelling, are available from the Royal College of Physicians website. Readers
involved in research in this field, and those who want to find the full rationale behind a
particular recommendation, will find this an invaluable resource.
The Department of Health, in commissioning this guideline, was clear that the focus was to be on
early detection and management. This is the area in which the guideline can deliver its greatest
potential benefit, through delaying progression of disease and thus reducing the need for dialysis
or transplantation. The key priority recommendations singled out in the guideline reflect this
emphasis. They present clear criteria for testing for CKD, suspecting progressive CKD, and
referring people for specialist assessment, all of which should be useful in primary care.
Recommendations are also provided on starting treatment once proteinuria has been assessed.
In common with other guideline topics in chronic conditions, there are some areas in CKD
which remain in need of good quality research to inform difficult clinical decisions. The GDG
have not shirked from addressing these questions and their expertise informed debates which
led to some forward-thinking recommendations, for example those dealing with testing for
proteinuria. For many practitioners a change in practice will be required as a result, but great
effort has been taken to explain the rationale for this change within the guideline, and to
demonstrate that the necessary effort is worthwhile.
As healthcare professionals in primary care take on an increasing role in the management of CKD,
it is hoped that this guideline will be a single useful and accessible reference promoting a
consistent high quality of care and hence improved quality of life for longer for people with CKD.
Dr Bernard Higgins MD FRCP
Director, National Collaborating Centre for Chronic Conditions
ix
AASK
ABLE
ACEI
ACR
Albumin:creatinine ratio
ACS
ADPKD
ALP
Alkaline phosphatase
ARB
ARIC
BMD
BMI
BNF
BP
Blood pressure
CABG
CAD
CARI
CHS
CRF
CRI
CURE
CI
Confidence interval
CKD
CrCl
Creatinine clearance
CV
Coefficient of variation
CVD
Cardiovascular disease
DBP
DMP
DNCSG
eGFR
ESRD
GDG
GFR
HDL
High-density lipoprotein
ICER
KEEP
HF
Heart failure
HR
Hazard ratio
HYP
Hypertension
IDMS
IDNT
IgA-GN
Immunoglobulin-A glomerulonephritis
iPTH
KDIGO
KDOQI
LDL
LDL-C
LPD
LVEF
MAP
MDRD
MI
Myocardial infarction
NCC-CC
NEOERICA
NHANES
NHS
NICE
NKF-KDOQI
NNS
NNT
NS
Non-significant
NSAIDs
NSF
NSTEACS
OR
Odds ratio
PCR
Protein:creatinine ratio
PREVEND
PTH
Parathyroid hormone
pmp
QOF
QALY
RBC
RCT
REIN RCT
RENAAL
xi
ROC
Receiver-operator curve
RR
Relative risk
RRT
SBP
SCr
Serum creatinine
SHARP
SIGN
SLT
STEACS
UKPDS
UPD
WMD
Glossary
xii
ACEI
Adverse events
Albuminuria
Algorithm
(in guidelines)
Allocation concealment
Audit
Bias
The effect that the results of a study are not an accurate reflection of
any trends in the wider population. This may result from flaws in
the design of a study or in the analysis of results.
Blinding (masking)
Case-control study
Clinical audit
Clinician
Cochrane review
Cohort study
Confidence interval (CI) A range of values which contains the true value for the population
with a stated confidence (conventionally 95%). The interval is
calculated from sample data, and generally straddles the sample
estimate. The 95% confidence value means that if the study, and the
method used to calculate the interval, is repeated many times, then
95% of the calculated intervals will actually contain the true value
for the whole population.
Cost-effectiveness
analysis
Diagnostic study
Evidence-based
healthcare
Follow up
Generalisability
Gold standard
Guideline development
group (GDG)
Haematuria
xiii
Heterogeneity
Homogeneity
Hyperkalaemia
Inclusion criteria
Incremental cost
Incremental cost
effectiveness ratio
(ICER)
Level of evidence
Macroalbuminuria
Meta-analysis
Methodological
limitations
Microalbuminuria
Multivariate model
National Collaborating
Centre for Chronic
Conditions (NCC-CC)
National Health
Service (NHS)
Negative predictive value The proportion of people with a negative test result who do not have
the disease.
xiv
Observational study
Odds ratio
Outcome
p values
Placebo
Positive predictive
value (PPV)
Proteinuria
Quality of life
Quality-adjusted
life year (QALY)
Randomisation
Randomised controlled
trial (RCT)
Reference standard
(or gold standard)
Sample size
xv
xvi
Sensitivity analysis
Serum creatinine
Specialist
Stakeholder
Statistical power
Statistical significance
Suffix (p)
Systematic review
Washout period
Withdrawal
DEVELOPMENT OF
THE GUIDELINE
1 Introduction
1.1
Background
Publication of the second part of the Renal National Service Framework (NSF)2 served to
emphasise the change in focus in renal medicine from treatment of established kidney disease
to earlier identification and prevention of kidney disease. Allied to this is the knowledge that
late referral of people with advanced kidney disease to nephrology services from both primary
and secondary care is still at least as high as 30%, engendering increased mortality and
morbidity38 and precluding assessment and preparation of those for whom conservative
management is more appropriate.
Over 2% of the total NHS budget is spent on renal replacement therapy (dialysis and
transplantation) for those with established renal failure.9 Strategies aimed at earlier
identification and (where possible) prevention of progression to established renal failure are
therefore clearly required. Equally importantly, population studies have shown that people with
diagnosed chronic kidney disease (CKD) have a far greater likelihood of cardiovascular death
than progression to established renal failure.1013 Furthermore, the majority of people with
CKD are asymptomatic and may not even be aware that they have any form of kidney problem.
The challenge is to:
G
identify people with or at risk of developing CKD
G
determine who needs intervention to minimise cardiovascular risk and to determine what
that intervention should comprise
G
determine who will develop progressive kidney disease and/or complications of kidney
disease and how they may be identified and managed to reduce/prevent these outcomes
G
determine who needs referral for specialist kidney care.
This requires adoption of an overall health approach (Figure 1.1) and an integrated care
strategy involving public awareness, professional education, policy influence, and improved
care delivery systems all under-pinned by research.
Complications
Normal
Increased
risk
Damage
GFR
Kidney
failure
Screening
for CKD
risk factors
CKD risk
factor
reduction,
screening
for CKD
Diagnosis
and treatment,
treat
comorbid
conditions,
slow
progression
Estimate
progression,
treat
complications,
prepare for
replacement
Replacement
by dialysis
and transplant
End-of-life
care
Figure 1.1 Chronic kidney disease: an overall health approach. GFR = glomerular filtration rate. (Reprinted by
permission from Macmillan Publishers Ltd: Kidney International, Levey AS, Atkins R, Coresh J et al. Chronic kidney disease as
a global health problem: approaches and initiatives a position statement from Kidney Disease Improving Global Outcomes.
Kidney International 2007; 72(3): 247259.14 Copyright 2007.)
A key component of the integrated care strategy is development of clinical guidelines which
synthesise a scientific understanding of the disease in terms of:
G
the disease prevalence
G
the ability to identify the disease and the people at risk
G
a knowledge of best therapies and strategies
G
the ability to deliver effective therapies in the right place at the right time with the right
tools.
In March 2006 the Joint Specialty Committee of the Royal College of Physicians of London and
the Renal Association, together with representatives from the Royal College of General
Practitioners, the Association for Clinical Biochemistry, the Society for District General
Hospital Nephrologists, the British Geriatric Society, the Professional Advisory Council of
Diabetes UK and the National Kidney Federation produced guidelines for the identification,
management and referral of adult people with CKD.15 Two further national strategies
promoting identification of CKD were implemented in April 2006: the automatic reporting of
an estimated glomerular filtration rate (eGFR) whenever a serum creatinine measurement is
requested of any clinical chemistry laboratory16 and the introduction of 4 renal domains in the
Quality and Outcomes Framework (QOF) subsequently updated in April 2008 (Table 1.1).17
These national strategies have raised questions that this guideline attempts to answer whilst
addressing the challenges detailed above.
Table 1.1 Quality and Outcomes Framework Guidance Chronic Kidney Disease Indicator
Set (updated April 2008)
1.2
Indicator 1
The practice can produce a register of patients aged 18 years and over with CKD (US National
Kidney Foundation: Stage 35 CKD)
Indicator 2
The percentage of patients on the CKD register whose notes have a record of blood pressure
in the previous 15 months
Indicator 3
The percentage of patients on the CKD register in whom the last blood pressure reading,
measured in the previous 15 months, is 140/85 mmHg or less
Indicator 5
The percentage of patients on the CKD register with hypertension and proteinuria who are
treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker
(ARB) (unless a contraindication or side effects are recorded)
Definition
The Renal NSF adopted the US National Kidney Foundation Kidney Disease Outcomes Quality
Initiative (NKF-KDOQI) classification of CKD. This classification divides CKD into five stages
(Table 1.2) defined by evidence of kidney damage and level of renal function as measured by
glomerular filtration rate (GFR). Stages 35 may be defined by GFR alone, whilst stages 1 and 2
also require the presence of persistent proteinuria, albuminuria, haematuria or structural
abnormalities. Stage 5 CKD may be described as established renal failure (also called end stage
renal disease (ESRD)), and is CKD which has progressed so far that renal replacement therapy
(regular dialysis treatment or kidney transplantation) may be required to maintain life.
Established renal failure is an irreversible, long-term condition. A small number of people with
established renal failure may choose conservative management only.
1 Introduction
The classification of CKD into 5 stages has been widely adopted but as understanding of the
epidemiology of CKD has developed, it has been criticised as not being sufficiently sophisticated
for clinical needs. For example, longitudinal population studies have suggested that stage 3 should
be subdivided into 3A and 3B. Other studies, underlining the importance of proteinuria/
albuminuria as an independent risk factor for adverse outcomes in CKD, suggest the adoption of
a (p) suffix in the different stages. This evidence and the changes to the classification that the
evidence suggests will be considered further in the relevant sections of the guideline.
Table 1.2 NKF-KDOQI stages of chronic kidney disease
Stage
Description
GFR (ml/min/1.73m2)
90
6089
3*
3059
1529
Kidney failure
1.3
Burden of disease
CKD is increasingly recognised as a public health problem and is usually characterised by an
asymptomatic period, which is potentially detectable. Tests for detecting CKD are both simple
and freely available and there is evidence that treatment can prevent or delay progression of
CKD, reduce or prevent development of complications, and reduce the risk of cardiovascular
disease (CVD). There is considerable overlap between CKD, diabetes and CVD and the risk of
developing CKD increases with increasing age. In assessing the burden of disease it is important
to understand the characteristics of our population.
The UK is an ageing and growing population. Since 1971 the population has increased by 7.7%
and since 2001 by 0.5% per annum such that the UK population in 2005 numbered 60,209,500
people.18 The mean age of the population in 1971 was 34.4 years and that had increased to 38.8
years with 16% of the population over 65 years of age in 2005 (Figure 1.2). The population is
also gaining weight; 67% of men and 58% of women are overweight. The population prevalence
of diabetes is 4%; 11.3% of the population are hypertensive; and although smoking rates have
decreased, 24% of the population aged over 16 are smokers (25% of men and 23% of women).
It is unsurprising that CVD remains prevalent: 3.6% of the population have coronary heart
disease, 1.5% cerebrovascular disease, and 0.4% congestive heart failure.
Age
90
80
70
60
50
Males
Females
40
30
20
10
0
500
250
250
Population (thousands)
Population (thousands)
500
Figure 1.2 Age and gender distribution of the UK population in 2005. (Source: Office for National Statistics
website: www.ons.gov.uk. Crown copyright material is reproduced with the permission of the Controller Office of Public Sector
Information (OPSI). Reproduced under the terms of the Click-Use Licence.)
Data from the UK Renal Registry9 indicate that there were 41,776 adult patients alive on renal
replacement therapy (RRT) in the UK at the end of 2005, a prevalence for adults of 694 per
million population (pmp). Addition of the 748 children under age 18 on RRT gives a total
prevalence of 706 pmp. There was a 5.0% annual increase in the prevalence of people on RRT
in the 38 renal units participating in the Registry since 2000. In 2005, the mean percentage of
patients referred late (less than 90 days before dialysis initiation) was still 30%, unchanged from
the value in 2000.
Whilst the UK Renal Registry provides accurate estimates of numbers of people undergoing
RRT, this cannot be seen as a surrogate for the number of people with stage 5 CKD, as the mean
GFR of those starting RRT is 7.5 ml/min/1.73 m2.
Information relating to the UK population prevalence of stage 35 CKD comes from a large
primary care study (practice population 162,113) suggesting an age standardised prevalence of
stage 35 CKD of 8.5% (10.6% in females and 5.8% in males). In these people the age- and
gender-adjusted odds ratio (OR) for hypertension was 2.1 (95% CI 2.02.2), for diabetes 1.33
(95% CI 1.211.41) and for CVD 1.69 (95% CI 1.591.79).19 The prevalence of CKD rose
dramatically with age (Figure 1.3).
1 Introduction
Male
Female
50
10
0
1824
2534
3544
4554
5564
6574
7584
84+
Although we have very little information about the total burden of CKD in the UK, data from the
National Health and Nutrition Examination Surveys (NHANES)20,21 in the USA not only gives a
guide to the likely overall population prevalence, but also suggests that the prevalence is
increasing. Comparison of the prevalence of CKD in NHANES 19881994 with NHANES
19992004 showed an increase in population prevalence from 10.03 to 13.07%.22 The overall
prevalence among men increased from 8.2% to 11.1% and in women from 12.1% to 15.0%. The
increased prevalence was partly explained by the increase in a number of CKD risk factors,
including an ageing population and an increase in obesity, diagnosed diabetes and hypertension.
It is important to note that the NHANES studies included only non-institutionalised people, and
the prevalence of CKD in nursing homes is likely to be significantly higher.
UK population studies have demonstrated that the risk of cardiovascular death in people with
diagnosed CKD far outweighs the risk of progression. A retrospective cohort study found that
only 4% of 1076 individuals progressed to end stage kidney disease over a 5.5 year follow-up
period whilst 69% had died at the end of follow-up; the cause of death was cardiovascular in
46% of cases.10 Similarly, a prospective cohort study of 3240 individuals with a median GFR of
28.5 ml/min/1.73m2 not known to renal services found that mortality was 39.5% after a median
follow-up period of 31.3 months. The cause of death was cardiovascular in 39.7% of cases. Only
8.3% of individuals sustained a decline in GFR greater than 5 ml/min/1.73m2/year during the
period of follow-up.11 This remarkable burden of cardiovascular disease in people with CKD,
and the relative lack of progression, has been confirmed in a number of observational
studies12,13 and is further illustrated by results from the New Opportunities for Early Renal
Intervention by Computerised Assessment (NEOERICA) project where 50% of those with a
stage 4 and 5 CKD had coexistent CVD which increased in prevalence as GFR decreased.19 The
magnitude of other comorbidities such as diabetes, hypertension and significant anaemia also
increased with more advanced kidney dysfunction (Table 1.3).
<30
N=525
3044
N=2475
4559
N=8731
>60
N=26531
50.7
42.7
27.1
14.8
Diabetes (%)
23.0
16.1
12
Hypertension (%)
87.8
86.6
71.4
47.1
10.0
4.1
2.9
2.7
9.4
Adapted and reprinted by permission from Macmillan Publishers Ltd: Kidney International (Stevens PE, ODonoghue DJ,
de Lusignan S et al. Chronic kidney disease management in the United Kingdom: NEOERICA project results. Kidney
International 2007; 72(1):9299).19 Copyright 2007.
The study of unreferred CKD by John et al. demonstrated that 85% of those with advanced
kidney dysfunction were unknown to renal services.11 The NEOERICA study serves to
underline this but also demonstrates that CKD is still largely unrecognised: only 2.1% of those
with a GFR less than 60 ml/min/1.73m2 had a coded diagnosis of renal disease.
A national programme to identify vulnerability to vascular diseases was announced by the
Secretary of State for Health in April 2008 following initial results from modelling work carried
out by the Department of Health. This work suggested that a vascular check programme would
prevent 4000 people a year from developing diabetes and could also detect at least 25,000 cases
of diabetes or kidney disease earlier.
It has long been recognised that the prevalence of established renal failure is higher amongst the
black and minority ethnic communities in comparison to Caucasian populations.23 The
predominant reasons for this include the increased prevalence of Type 2 diabetes in South
Asians and hypertension in African Caribbeans, together with diseases particular to certain
communities such as chronic interstitial nephritis in South Asians and focal glomerulosclerosis
in African Caribbeans. However, there is a relative lack of knowledge concerning the prevalence
of earlier stages of CKD in black and ethnic minority populations in comparison to Caucasians.
In the United States, the racial disparity in the incidence of established renal failure among
black compared with white populations is not reflected in the prevalence of less severe degrees
of impaired kidney function.24 Similar findings have been reported from the NHANES III data.
It has been suggested that the reasons for this disparity lie with racial differences in the rate of
progression to established renal failure. The ABLE projects (A Better Life through Education
and Empowerment) in the UK have also demonstrated that kidney disease in South Asians and
African Caribbeans may deteriorate more rapidly to established renal failure.25 In the long
term, the ABLE study aims to identify the reasons for this faster deterioration.
2 Methodology
2.1
Aim
The aim of the National Collaborating Centre for Chronic Conditions (NCC-CC) is to provide
a user-friendly, clinical, evidence-based guideline for the National Health Service (NHS) in
England and Wales that:
G
offers best clinical advice for the early identification and management of CKD in adults in
primary and secondary care
G
is based on best published clinical and economic evidence, alongside expert consensus
G
takes into account patient choice and informed decision-making
G
defines the major components of NHS care provision for CKD
G
details areas of uncertainty or controversy requiring further research and
G
provides a choice of guideline versions for different audiences.
2.2
Scope
The guideline was developed in accordance with a scope which detailed the remit of the
guideline originating from the Department of Health and specified those aspects of CKD care
to be included and excluded.
Prior to the commencement of the guideline development, the scope was subjected to
stakeholder consultation in accordance with processes established by the National Institute for
Health and Clinical Excellence (NICE).1 The full scope is shown in Appendix B.
2.3
Audience
The guideline is intended for use by the following people or organisations:
G
all healthcare professionals
G
people with CKD and their carers
G
patient support groups
G
commissioning organisations and
G
service providers.
2.4
2.5
consulting the Patient and Public Involvement Programme (PPIP) housed within NICE
during the pre-development (scoping) and final validation stages of the guideline project
and
the inclusion of patient groups as registered stakeholders for the guideline.
Guideline limitations
Guideline limitations are as follows:
G
NICE clinical guidelines usually do not cover issues of service delivery, organisation or
provision (unless specified in the remit from the Department of Health).
G
NICE is primarily concerned with health services and so recommendations are not
provided for social services and the voluntary sector. However, the guideline may address
important issues in how NHS clinicians interface with these sectors.
G
Generally, the guideline does not cover rare, complex, complicated or unusual conditions.
G
It is not possible in the development of a clinical guideline to complete extensive
systematic literature review of all pharmacological toxicity. NICE expects the guidelines to
be read alongside the summaries of product characteristics.
2.6
2.7
Background
The development of this evidence-based clinical guideline draws upon the methods described
by the NICE Guidelines manual1 (see http://www.nice.org.uk). The developers role and remit
is summarised in Table 2.1.
10
2 Methodology
The NCC-CC was set up in 2001 and is housed within the Royal College
of Physicians (RCP). The NCC-CC undertakes commissions received
from the National Institute for Health and Clinical Excellence (NICE).
A multiprofessional partners board inclusive of patient groups and
NHS management governs the NCC-CC.
The technical team met approximately two weeks before each Guideline
Development Group (GDG) meeting and comprised the following
members:
GDG Chair
GDG Clinical Advisor
Information Scientist
Research Fellow
Health Economist
Project Manager.
The GDG met monthly (January 2007 to February 2008) and comprised
a multidisciplinary team of health professionals and people with
chronic kidney disease, who were supported by the technical team.
The GDG membership details including patient representation and
professional groups are detailed in the GDG membership table at the
front of this guideline.
Formal consensus
Members of the GDG declared any interests in accordance with the NICE Guidelines manual.1 A register is
given in Appendix D, available online at http://www.rcplondon.ac.uk/pubs/brochure.aspx?e=257
2.8
12
2 Methodology
The health economist performed supplemental literature searches to obtain additional data for
modelling. Assumptions, data and structures of the models were explained to and agreed by the
GDG members during meetings, and they commented on subsequent revisions.
Type of evidence
1++
1+
Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias.
2++
2+
Case-control or cohort studies with a high risk of confounding, bias or chance and a
significant risk that the relationship is not causal.*
*Studies with a level of evidence should not used as a basis for making a recommendation.
13
14
2 Methodology
NICE version
An abridged version.
Available at http://www.nice.org.uk
Understanding NICE
guidance
2.9
Disclaimer
Healthcare providers need to use clinical judgement, knowledge and expertise when deciding
whether it is appropriate to apply guidelines. The recommendations cited here are a guide and may
not be appropriate for use in all situations. The decision to adopt any of the recommendations
cited here must be made by the practitioner in light of individual patient circumstances, the wishes
of the patient, clinical expertise and resources.
The NCC-CC disclaims any responsibility for damages arising out of the use or non-use of
these guidelines and the literature used in support of these guidelines.
2.10 Funding
The National Collaborating Centre for Chronic Conditions was commissioned by the National
Institute for Health and Clinical Excellence to undertake the work on this guideline.
15
Offer ACEI/ARBs to non-diabetic people with CKD and hypertension and ACR 30 mg/mmol
(approximately equivalent to PCR 50 mg/mmol, or urinary protein of 0.5 g/day).
Stage 3 CKD should be split into two subcategories defined by:
G
GFR 4559 ml/min/1.73 m2 (stage 3A)
G
GFR 3044 ml/min/1.73 m2 (stage 3B).
People with CKD should usually be referred for specialist assessment if any of the following apply:
G
stage 4 and 5 CKD (with or without diabetes)
G
heavy proteinuria (ACR 70 mg/mmol, approximately equivalent to PCR 100 mg/mmol,
or urinary protein excretion 1 g/24 h) unless known to be due to diabetes and already
appropriately treated
G
proteinuria (ACR 30 mg/mmol, approximately equivalent to PCR 50 mg/mmol, or
urinary protein excretion 0.5 g/24 h) together with haematuria
G
rapidly declining eGFR (>5 ml/min/1.73m2 in one year, or >10 ml/min/1.73m2 within
5 years)
G
hypertension that remains poorly controlled despite the use of at least 4 anti-hypertensive
drugs at therapeutic doses (see NICE clinical guideline 34, Hypertension: management of
hypertension in adults in primary care)
G
a rare or genetic cause of CKD, or the suspicion of one
G
suspected renal artery stenosis.
Offer people testing for CKD if they have any of the following risk factors:
G
diabetes (types 1 and 2)
G
hypertension
G
cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular
disease and cerebral vascular disease)
G
structural renal tract disease, renal calculi or prostatic hypertrophy
G
multisystem diseases with potential kidney involvement, e.g. systemic lupus
erythematosus (SLE)
G
family history of stage 5 CKD or hereditary kidney disease.
Take the following steps to identify progressive CKD:
G
obtain a minimum of three glomerular filtration rate (GFR) estimations over a period of
not less than 90 days
G
in people with a new finding of reduced eGFR, repeat the estimated glomerular filtration
rate (eGFR) within 2 weeks to exclude causes of acute deterioration of GFR, e.g. acute
kidney injury or initiation of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin
receptor blocker (ARB) therapy
17
In people with CKD, aim to keep the systolic blood pressure below 140 mmHg (target range
120139 mmHg) and the diastolic blood pressure below 90 mmHg.
18
3.2
Algorithms
Progression of CKD
Stages of CKD
Stage 1 and 2
Stage 3A
Stage 3B
Stage 4
Stage 5
Figure 3.1 Investigations and interventions at different stages of CKD. This algorithm should be used as an aide memoire in primary
care to trigger various investigations and interventions relevant for people in different stages of CKD. Stages of CKD are shown from left to right and
activities appear as horizontal bands, some of which are more relevant to early or late disease, as indicated by their positioning and by the graded
shading. BP = blood pressure; NSAID = non-steroidal anti-inflammatory drug; PTH = parathyroid hormone.
19
Targeted identification
Targeted identification
Risk factors for CKD (excluding diabetes) including:
hypertension
nephrotoxic drugs, e.g. lithium, calcineurin inhibitors,
chronic NSAID use
cardiovascular disease
structural renal tract disease, renal calculi or prostatic
hypertrophy
family history of stage 5 CKD or hereditary kidney disease
multisystem disease with potential kidney involvement,
e.g. SLE
opportunistic haematuria or proteinuria
If none of the above, do not use age, gender or ethnicity
as risk markers.
Protein in
urine
Exclude
infection or
urological
cause
Measure eGFR
Send urine for ACR (or PCR)
Monitor GFR in people
prescribed drugs known
to be nephrotoxic such as
calcineurin inhibitors and
lithium.
Check GFR at least
annually in people
receiving long-term
systemic NSAIDs.
Blood in
urine
Blood results
eGFR 60
No risk factors for
CKD
Urine results
eGFR 60
Risk factors for CKD
eGFR 3059
eGFR <30
Confirmed by a
Confirmed by a
repeat test within repeat test within
14 days
14 days
Repeat eGFR in
12 months
ACR 70
or PCR 100
Figure 3.2 Identification, diagnosis and referral of patients with CKD but without diabetes. eGFR is expressed as ml/min/1.73m2.
Albumin:creatinine ratio (ACR) and protein:creatinine ratio (PCR) are expressed as mg/mmol.
20
Refer to
renal specialist
Blood results
eGFR >60
eGFR 3059
or
Reassess patient
annually
Obtain eGFR and ACR
eGFR <30
Manage according to
recommendations for
non-diabetic renal
disease according to
stage of disease
Follow NICE guidelines
15 and 66
Including referral
Refer to renal specialist
Urine results
Refer to:
diabetes specialist
renal specialist if
suspicion of nondiabetic renal disease
Refer to renal
specialist
*See NICE clinical guidelines on type 1 diabetes (http//:www.nice.org.uk/CG15) and type 2 diabetes (http//:www.nice.org.uk/CG66).
Figure 3.3 Diagnosis and referral of patients with CKD and diabetes. eGFR is expressed as ml/min/1.73m2. Albumin:creatinine ratio
(ACR) is expressed as mg/mmol.
21
THE GUIDELINE
4 Investigation of CKD
4.1
4.1.1
Clinical introduction
The glomerular filtration rate (GFR) is equal to the sum of the filtration rates in all of the
functioning nephrons and is the best index of overall kidney function. Knowledge of GFR is
essential for the diagnosis and management of CKD and is a translatable concept. Because a
normal GFR is roughly 100 ml/min/1.73 m2, we can explain kidney function to patients and
carers in terms of a percentage of normal a more easily understandable concept than GFR.
The gold standard methods of estimating GFR require measurement of an ideal filtration
marker. These markers should be freely filtered by the glomerulus, should not be bound to
plasma proteins, must be excreted unchanged and not be subject to either tubular secretion or
absorption. Commonly used markers include inulin, 51Cr-EDTA, 125I-iothalamate and iohexol.
Gold standard methods of assessing GFR are technically demanding, expensive, time
consuming and unsuitable for widespread identification of CKD in the at risk population.
At the other end of the accuracy scale lies measurement of serum creatinine, which is a
universally available endogenous test of kidney function. Although easy and cheap to measure,
creatinine is subject to non-renal and analytical influences which make it insufficiently sensitive
to detect moderate CKD on its own. Measurement of 24-hour urinary creatinine clearance
improves the accuracy but is also subject to the same non-renal and analytical influences
compounded by inaccuracies in urine collection, to say nothing of the inconvenience associated
with 24-hour urine collections. An alternative and more accurate endogenous marker is
cystatin C, a 13 kDa cationic protein produced by all nucleated cells. Serum cystatin C levels are
chiefly determined by GFR. Potential limitations of cystatin C as a marker of GFR include lack
of assay standardisation, the requirement for a dedicated analytical system, and increased costs
relative to serum creatinine (approximately 3/assay compared to <0.10/assay).
A further alternative is to measure serum creatinine and estimate GFR using an equation which
corrects for some of the more significant non-renal influences. This approach is known to be
more sensitive for the detection of CKD than serum creatinine and more accurate than
creatinine clearance.
So what have previous guideline groups recommended? The SIGN guidelines32 recommended
use of prediction equations in place of 24-hour creatinine clearance or serum creatinine alone
and preferred prediction equations to cystatin C on the grounds of practical and resource
considerations. The Modification of Diet in Renal Disease (MDRD) equation was preferred to
the Cockcroft-Gault formula. The UK CKD guidelines and the UK consensus conference
recommended use of the 4-variable MDRD equation using zero biased creatinine methods.33,34
Others (KDOQI, CARI and KDIGO)14,3537 have recommended that serum creatinine should
not be used alone to assess kidney function, that creatinine assays should be traceable to a
reference creatinine method, and that an estimated GFR should be reported by laboratories
alongside the serum creatinine measurement using the 4-variable MDRD equation.
What is the best diagnostic test to measure renal function in routine clinical practice?
25
4.1.2
Methodology
Due to the large volume of studies in this area, studies were included if the sample size was
greater than 100, gold standard tests were used as the reference test, and bias, accuracy,
sensitivity, specificity, positive and negative predictive values, test correlation, or diagnostic
accuracy (area under the receiveroperator curve (ROC)) outcomes were reported. For studies
comparing the MDRD predictive equation with other equations, the serum creatinine
measurements had to be calibrated to the MDRD laboratory reference standard. Two
exceptions to the sample size cut-off were the studies that evaluated the GFR equations in older
people.38,39 Publications that reported on the accuracy of tests in dialysis or renal replacement
patients were excluded.
Five studies4044 that evaluated the accuracy of serum cystatin C were excluded because gold
standard tests were not used as the comparator or because creatinine (the MDRD equation) was
not calibrated properly to the MDRD laboratory reference values.
Nine studies3841,4549 that evaluated the accuracies of predictive equations in estimating GFR
were excluded due to methodological limitations or because the serum creatinine measurements
were not calibrated to the MDRD assay as determined by isotope-dilution mass spectrometry.
Five studies5054 assessing the accuracies of the MDRD equation and the Cockcroft-Gault
equation in predicting the glomerular filtration rate were included. These were conducted in
large sample sizes (N=219 to 2095) and were quite heterogeneous in terms of the population
studied: older populations, diabetic nephropathy, mild renal impairment, moderate renal
impairment, or healthy populations. Differences in performances of the equations may be
explained by the different populations in which the equations were derived, and multiple
sources of measurement variation when measuring creatinine.
4.1.3
4.1.4
s
Evidence statements
Cystatin C concentration versus predictive equations (MDRD or Cockcroft-Gault)
Two cross-sectional studies40,41 that compared cystatin C to the MDRD and Cockcroft-Gault
equations were excluded because the serum creatinine measurements were not calibrated to the
MDRD assay.
26
4 Investigation of CKD
Study
Evidence
level
N
Bias
(ml/min/1.73m2)
Sensitivity
(%)
52
1b +
2095
(CKD +
kidney
donors)
MDRD
0.99 ml/min/
1.73 m2, p=0.001
CG 1.94 ml/min/
1.73 m2, p<0.0001
Bias was greater
for MDRD equation
(6.2 ml/min/1.73 m2)
than the CockcroftGault equation
(0.3 ml/min/1.73 m2)
in patients with a
measured GFR
>90 ml/min/1.73 m2.
The MDRD equation
was less biased than
the Cockcroft-Gault
equation in patients
with stage 3, 4, or
5 CKD.
The MDRD equation
was significantly less
biased than the
Cockcroft-Gault
equation when
patients were analysed
by age (above or
below 65 years) and
gender (p<0.0001).
51
1b +
219
(CKD +
nonCKD)
53
II +
54
50
Test correlation
with gold
standard
Specificity (%)
Accuracy (P30)
MDRD
(78.9%) ,
CG (67.6%) in
stage 4 CKD
MDRD (64.8%)
CG (43%) in
stage 5 CKD
MDRD 92%
MDRD (r=0.910)
CG 88% in
Cockcroft-Gault
people with
(r=0.894)
GFR >60 ml/min/
1.73 m2.
People with
GFR <60 ml/min/
1.73 m2 (82%
MDRD versus
69% CockcroftGault).
NR
NR
MDRD 62% vs
CG 48.8%,
p<0.01
1286
MDRD 22 vs
(type 1
CG 6
diabetes)
NR
NR
When GFR
NR
>120 MDRD 97%
CG 87%,
p<0.001.
When
GFR <120
MDRD 82%
CG 92%, p<0.001
1b +
1628
(CKD)
MDRD 0.2 vs
CG 7.3
When GFR >90
MDRD 3.0 vs
CG 21.8
MDRD 97 vs
CG 85,
p<0.001
MDRD 70 vs
CG 88, p<0.001
MDRD 90%
(95% CI 8991)
vs CG 60%
(95% CI 5862)
NR
1b +
828
(CKD)
457
(kidney
donors)
MDRD 0.5 vs
CG 3.5, p< 0.001
NR
NR
MDRD 71%
CG 60%,
p<0.001
CKD group:
MDRD (r=0.90)
and CG (r=0.89).
Kidney donor
control group:
MDRD (r=0.36)
CG (r=0.41)
NR
NR = not reported.
27
Test correlation
Regression analysis was used to determine the correlation between GFR measured by the gold
standard test and GFR calculated using the MDRD or Cockcroft-Gault predictive equations.
Two studies50,52 showed that both the MDRD and Cockcroft-Gault equations correlated highly
with the measured GFR in people with CKD, often with no statistical difference between the
correlation coefficients for the MDRD and Cockcroft-Gault equations. Both MDRD and
Cockcroft-Gault equations correlated poorly with the gold standard test in renal donors. 50
(Level 1b +)
Bias
In diabetic populations53 and in CKD populations,50,51 the MDRD equation often underestimated the measured GFR. The Cockcroft-Gault equation often overestimated the GFR.
(Level 1b +)
In CKD populations, the MDRD equation was superior to the Cockcroft-Gault equation in
terms of bias.50,52,54 The MDRD equation slightly underestimated the measured GFR, while the
Cockcroft-Gault equation significantly overestimated the GFR (0.5 vs. 3.5 ml/min/1.73 m2,
p<0.001). The MDRD equation was also significantly less biased than the Cockcroft-Gault
equation in the nondiabetic CKD (N=579) subgroup, the diabetic CKD (N=249) subgroup,
and in people with a measured GFR <30 ml/min/1.73 m2 (N=546) (p<0.001 in each group).
(Level 1b +)
The MDRD and Cockcroft-Gault equations were significantly more biased in people with GFR
>60 ml/min/1.73 m2 (N=117). The MDRD equation underestimated the measured GFR, while
the Cockcroft-Gault equation significantly overestimated the GFR (3.5 vs. 7.9 ml/min/
1.73 m2, p<0.001). In the kidney donor control group (N=459), the Cockcroft-Gault equation
was superior to the MDRD equation in terms of bias (1.9 vs. 9.0 ml/min/1.73 m2, p<0.001).50
(Level 1b+)
Accuracy (P30)
Five studies5054 reported the percentage of estimated GFR values falling within 30% of the
GFR values measured by the gold standard test. Generally, the MDRD equation was more
accurate than the Cockcroft-Gault equation. (Level 1b+)
28
4 Investigation of CKD
4.1.5
4.1.6
RECOMMENDATIONS
R1
Whenever a request for serum creatinine measurement is made, clinical laboratories should
report an estimate of GFR (eGFR) using a prediction equation (see recommendation R2) in
addition to reporting the serum creatinine result.*
R2
Use the isotope dilution mass spectrometry (IDMS)-traceable simplified MDRD equation to
estimate GFR, using creatinine assays with calibration traceable to a standardised reference
material. Ideally use creatinine assays that are specific and zero-biased compared to IDMS
(e.g. enzymatic assays). When non-specific assays are used (e.g. Jaffe assays), employ
appropriate assay-specific adjustment factors to minimise between-laboratory variation
(e.g. those provided by national external quality assessment schemes).
R3
Where indicated, apply a correction factor for ethnicity to reported GFR values (multiply
eGFR by 1.21 for African-Caribbean ethnicity).**
R4
Interpret reported values of eGFR 60 ml/min/1.73m2 with caution, bearing in mind that
estimates of GFR become less accurate as the true GFR increases.
*
eGFR may be less reliable in certain situations (for example, acute renal failure, pregnancy, oedematous
states, muscle wasting disorders, amputees and malnourished people) and has not been well validated in
certain ethnic groups (for example, Asians and Chinese).
** In practice this correction factor should also be applied to those of African ethnicity.
29
R5
R6
R7
In cases where there are extremes of muscle mass (e.g. body builders, amputees, muscle
wasting disorders) interpret the eGFR with caution. (Reduced muscle mass will lead to overestimation and increased muscle mass to under-estimation).
4.2
4.2.1
Clinical introduction
The measurement of serum creatinine to estimate GFR with predictive equations is subject to
biological and analytical variation.
Biological variation includes random variation and predictable cyclical variation (daily, monthly,
seasonal). Within-subject biological variation is the average random fluctuation around a
homeostatic set point, expressed mathematically as a coefficient of variation (CV).55 Large
variations in serum creatinine measurements could result in misclassification of people to a
particular CKD stage. Factors affecting measured serum creatinine concentration and estimated
GFR from prediction equations include ingestion of cooked meat (where the cooking process
converts meat creatine to creatinine, which is subsequently absorbed into the bloodstream after
ingestion), individual patient fluid status, diurnal variation, and centrifugation of blood samples.
Plasma creatinine measurements also vary depending on the method/analyser used and there is
inter-laboratory variation which changes with creatinine concentration. There is no (single)
standard method used across England. Method precision at higher levels of creatinine has less
variability and thus has marginal impact on the interpretation of eGFR from prediction
equations. However, in the critical diagnostic range there is concern that inter-method/laboratory
variation may impact on the diagnostic utility of eGFR. This is probably at creatinine
concentrations of less than 180 mol/l. If creatinine levels are overestimated because of method
bias/variability this will result in a reduced eGFR (false positives) and misclassification of CKD.
This will lead to increased referral rates and inappropriate labelling of patients as having CKD. If
creatinine levels are underestimated, the reverse will happen (false negatives).
Since April 2006, creatinine assays in chemistry laboratories in England have been calibrated to
the gold standard reference method of isotope dilution mass spectrophotometry (IDMS)
through the National External Quality Assurance Scheme. This has enabled reporting of an
IDMS-related MDRD derived eGFR to minimise interlaboratory variation in GFR results. This
section addresses other sources of bias and variation in creatinine measurement.
4.2.2
In adults with CKD, what is the biological and analytical variability in eGFR testing and what
factors (including fasting) affect it?
Methodology
Three case series investigated the biological and analytical variation of serum creatinine
measurements in people with CKD56,57 or with type 1 diabetes.58
30
4 Investigation of CKD
Two studies examined the effect of delayed centrifugation of outpatient blood samples on the
measurement of serum creatinine concentration by the kinetic Jaffe reaction or by enzymatic
methods. The effect of delayed centrifugation of blood samples on GFR estimation was
determined.59,60
Two case series investigated the diurnal variation in serum creatinine measurements in
72 patients with varying degrees of renal disease61 and in 9 healthy people.62
Two case series evaluated the effect of a cooked meat meal on serum creatinine concentration
in healthy subjects and outpatients63 or in adults with diabetic nephropathy.64 Two earlier
studies examined changes in serum creatinine following ingestion of relatively large portions of
cooked meat (300g) or raw meat (300g) or non-meat meals in six healthy volunteers.65,66
4.2.3
4.2.4
s
Evidence statements
Biological variation of serum creatinine
The intra-individual biological variation of creatinine measurements was significantly higher in
people with CKD (N=17, coefficient of variation (CV)=5.3%) than in healthy people (N=24,
CV=2.7%, p<0.01).57
The CV for serum creatinine for nine people with CKD on all occasions was 61.9%. The average
analytical variation for serum creatinine was 0.1% of the total variance. The average intraindividual biological variation of creatinine measurements was 1.1% of the total variance.56
(Level 3)
The intra-individual biological variation of creatinine measurements was significantly higher in
women with type 1 diabetes (N=11, CV=6.53%) than in healthy women (N=14, CV=2.81%,
p<0.01). The intra-individual biological variation of creatinine measurements was significantly
higher in men with type 1 diabetes (N=16, CV=5.88%) than in healthy men (N=10, CV=2.64%,
p<0.01). 58 (Level 3)
creatinine concentration significantly increased (86 mol/l at baseline to 175 mol/l 3 hours
postprandially, p<0.001). The creatinine levels then declined and at 10 hours postprandially, the
levels stabilised, but did not return to baseline levels. Following a non-meat meal or a raw beef
meal, the serum creatinine concentration was relatively unchanged.65 (Level 3)
Following a cooked meat breakfast (N=6), the mean serum creatinine concentration
significantly increased from baseline to 2 to 4 hours postprandially (52% increase, range
3665%). The creatinine levels slowly declined and returned to baseline by 12 hours. By
contrast, following either a high or low non-meat protein breakfast (control), serum creatinine
remained stable.66 (Level 3)
In 10 people with diabetic nephropathy, the mean serum creatinine concentration significantly
increased from baseline (167 mol/l) to 180 mol/l in 2 hours (p<0.001) following a cooked
meat meal.64 (Level 3)
Following a cooked meat lunch (N=32 healthy volunteers and outpatients), the median serum
creatinine concentration significantly increased from baseline by 18.5 mol/l 3 to 4 hours
postprandially (p<0.0001). The median eGFR significantly decreased from baseline by 20 ml/min/
1.73 m2 3 to 4 hours postprandially (p<0.0001). Following a meat meal, 11 people changed from
a pre-prandial eGFR >59 ml/min/1.73 m2 to a postprandial eGFR of <60 ml/min/1.73 m2,
erroneously placing them in stage 3 CKD. By contrast, following a vegetarian lunch (N=23), there
was a NS change in median serum creatinine concentration; and there was a small but significant
increase in eGFR from baseline (preprandial) to 34 hours postprandially (3.5 ml/min/1.73 m2,
p=0.006).63 (Level 3)
4.2.5
32
4 Investigation of CKD
recently eaten meat. Serum creatinine concentrations also show diurnal variation. This means that
the eGFR derived using the 4-variable MDRD equation will also be affected by these factors.
When making a diagnosis of CKD, assessing the stage of CKD, or monitoring patients for
evidence of declining kidney function, it is important that clinicians are aware of the factors
that can influence creatinine concentrations. It was recommended that whenever possible they
take steps to minimise the biases that these factors introduce and that they are aware that
changes of less than 5% may simply be due to biological and analytical variability.
Whilst a simple solution to the variability introduced by eating meat would be to recommend
an overnight fast before having a blood sample taken, it was agreed that this was unnecessarily
restrictive.
4.2.6
RECOMMENDATIONS
R8
Advise people not to eat any meat in the 12 hours before having a blood test for GFR
estimation. Avoid delaying the despatch of blood samples to ensure that they are received and
processed by the laboratory within 12 hours of venepuncture.
R9
12 monthly
3A and 3B
3059
6 monthly
1529
3 monthly
<15
6 weekly
Stage
1 and 2
The information in this table is based on GDG consensus and not on evidence.
4.3
4.3.1
Clinical introduction
The persistent presence of protein (proteinuria), albumin (albuminuria), or red blood cells
(haematuria) in urine is evidence of kidney damage. Diagnostic tests that can rapidly detect the
presence of protein or red blood cells in urine with high specificity and sensitivity are integral
to the early detection and management of CKD.
Haematuria is defined as the presence of red blood cells (RBCs) in the urine, either visible
(macroscopic haematuria) or invisible and detected by direct microscopy (microscopic
haematuria). A reagent strip test to detect blood in urine provides an instant result and is often
the method of detection of invisible haematuria in the primary care setting.67 The reagent strip
33
or dipstick test is commonly considered to be sensitive for the detection of RBCs below the
defined (microscopic) 3 RBCs per high power field threshold for invisible haematuria. Dipstick
testing of spot urine samples is also used for rapid detection of protein and albumin. However,
reagent strips are subject to false positives because of patient dehydration, exercise, infection,
and extremely alkaline urine. False negative results occur as a result of excessive hydration and
urine proteins other than albumin.
Haematuria can be broadly classified as nephrological or urological in origin. Most forms of
intrinsic kidney disease may result in invisible haematuria. Urological causes include tumours,
urinary tract infection, stone disease and bleeding from benign conditions of the urinary tract.
Invisible haematuria may also be detected in the absence of any underlying pathology, such as
after vigorous exercise.68 The prevalence of asymptomatic invisible haematuria varies between
0.19% and 21%, depending on age and gender. Screening studies have suggested that the
prevalence of asymptomatic invisible haematuria in the UK adult male population is around
2.5%, increasing to 22% in men over the age of 60 years.69,70
Detection of clinical proteinuria at the point of care using dipsticks is usually defined by a
colour change of + or greater on the relevant pad on the strip device. This is thought to equate
to approximately 300 mg/l of total protein or an excretion rate of 450 mg/24 h. Reagent strip
devices for proteinuria detection have been in clinical use for approximately 50 years but they
have significant limitations. They rely on estimation of protein concentration which is
dependent on urine flow rate. Concentrated urine may yield a colour change in the positive
range even though protein excretion rate remains normal. Conversely, dilute urine may mask
significant proteinuria. Also, the performance of the dipsticks is operator-dependent and
affected by the presence of certain drugs and urinary pH. Finally, although purporting to
measure total protein, most protein strips are predominantly sensitive to albumin.
The purpose of this section was therefore to evaluate the efficacy of reagent strip tests to detect
haematuria and proteinuria/albuminuria and determine their diagnostic accuracy.
I
4.3.2
What is the sensitivity and specificity of reagent strips for detecting protein and blood in urine?
Methodology
Much of the published research that aims to detect or quantify protein or albumin in urine uses
24-hour urinary protein or albumin excretion as a gold standard. However there are important
reservations to be borne in mind regarding this technique. The 24-hour timed urine sample is
subject to inaccurate sample collection, low patient compliance, expense, and time requirement,
making this test difficult to implement as a routine test in a primary care setting. Other ways of
detecting proteinuria are the protein:creatinine ratio (PCR) or albumin:creatinine ratio (ACR) in
a spot urine sample. But, as has been discussed in the clinical introductions, it is not yet established
whether proteinuria or albuminuria best predicts progression of CKD in people who do not have
diabetes. It is therefore not necessarily helpful to know that a more practical measurement such as
protein:creatinine ratio correlates with 24-hour protein. Another caution required in interpreting
the evidence base is that albumin is one component of the protein detected, and although the
proportion varies between individuals, particularly at low levels of proteinuria, it is not surprising
to find protein measurements correlating reasonably with albumin measurements. Finally, a
certain amount of the agreement between ACR and PCR will be attributable to the creatinine
measurement for each individual, which is the denominator of each ratio.
ACR and PCR have been shown to correlate with the 24-hour albumin or protein excretion rate.
Proteinuria is defined as a 24-hour protein excretion rate 150 mg/24 h. Microalbuminuria is
34
4 Investigation of CKD
4.3.3
4.3.4
Evidence statements
Detection of haematuria
Study
Population
74
Hospitalised
patients
N=100
825
N-Multistix-SG vs
samples phase-contrast
microscopy of
un-spun urine
71
Systemic
269
lupus
erythematosus
Comparison
Hemastix vs
phase-contrast
microscopy of
urinary sediment
Number
of true
positives
Sensitivity Specificity
(%)
(%)
PPV (%)
NPV
(%)
Trace
RBC
98
Cut-off
63/269 =
24%
82%
100%
53
39
99
35
The sensitivity of reagent strips for detecting trace erythrocytes in urine of adults with lupus
(N=269) was high (98%), but the specificity (53%) and PPV (39%) were low.71 In hospitalised
patients (N=100, 825 urine samples) the PPV for trace and + results on a reagent strip were
82% and 100% respectively.74 (Level 1b +)
Detection of albuminuria
Sensitivity
(%)
Specificity
(%)
PPV (%)
NPV
(%)
Study
Population
Comparison
Cut-off
75
Hospitalised
patients
310
Multistix PRO vs
ACR
ACR
80 mg/g
creatinine
NR
84
89
75
Kidney
disease
113
Multistix PRO vs
ACR
ACR
80 mg/g
creatinine
73/113 =
65%
86
100
75
People with
diabetes
80
Multistix PRO vs
ACR
ACR
80 mg/g
creatinine
19/80 =
24%
83
100
78
Hypertensive
adults
79
Micraltest II vs
28.2 mg/L 4/79 = 5%
24-h nephelometry
(albumin)
75
95
43
99
78
People with
diabetes
166
Micraltest II vs
30.5 mg/L 71/166 =
24-h nephelometry
42%
(albumin)
83
96
95
88
76
General
population
(Japan)
2321
Multistix vs ACR
ACR
30 mg/g
creatinine
317/2321
= 14%
(ACR 30
300 mg/g)
37 (trace
proteinuria
defined as
+)
97 (trace
proteinuria
defined as
+)
71 (trace
proteinuria
defined
as +)
90 (trace
proteinuria
defined
as +)
76
People with
diabetes
(Japan)
201
Multistix vs ACR
ACR
30 mg/g
creatinine
317/2321
= 14%
(ACR 30
300 mg/g)
45 (trace
proteinuria
defined as
+)
98 (trace
proteinuria
defined as
+)
91 (trace
proteinuria
defined
as +)
76 (trace
proteinuria
defined as
+)
76
Hypertensive 1323
adults (Japan)
Multistix vs ACR
ACR
30 mg/g
creatinine
317/2321
= 14%
(ACR 30
300 mg/g)
37 (trace
proteinuria
defined as
+)
98 (trace
proteinuria
defined
as +)
81 (trace
proteinuria
defined
as +)
86 (trace
proteinuria
defined as
+)
77
People with
diabetes
Micral-Test II vs
Urinary albumin
concentration
(radioimmunoassay)
Albumin
concentration
<20 mg/l
114/411 = 93
28% (UAC
20200 mg/l);
47/411 =
11% (UAC
>200 mg/l)
93
89
36
411
4 Investigation of CKD
Overall, the sensitivity of reagent strips for detecting albuminuria was low. The specificity of
reagent strips for detecting albuminuria was high, ranging from 9398%. (Level 1b+)
Overall, the positive predictive values of the reagent strips for detecting albuminuria were low,
ranging from 7191%. (Level 1b+)
The negative predictive value of reagent strips varied according to the cut-off value used to
define albuminuria. (Level 1b+)
Detection of proteinuria
Cut-off
Number
of true
positives
Sensitivity
(%)
Specificity
(%)
PPV (%)
NPV
(%)
62%
49
94
Study
Population
Comparison
85
Kidney
disease
297
Multistix 10 SG
0.150 g/
vs 24-hour protein 24 h
excretion
86
Kidney
disease
332
Multistix 10 SG
vs PCR
100 (when
reagent
strip result
+1)
60 (when
reagent
strip result
+1
86
Kidney
disease
332
Multistix 10 SG
vs PCR
96 (when
reagent
strip result
+3)
87 (when
reagent
strip result
+3)
86
Kidney
disease
332
Multistix 10 SG
vs PCR
94 (when
reagent
strip result
+4)
83 (when
reagent
strip result
+4)
75
Hospitalised
patients
310
Multistix PRO vs
PCR
PCR
300 mg/g
creatinine
NR
84
87
75
Kidney
disease
113
Multistix PRO vs
PCR
PCR
300 mg/g
creatinine
81/113 =
72%
92
93
75
People with
diabetes
80
Multistix PRO vs
PCR
PCR
300 mg/g
creatinine
20/80 =
25%
83
98
88
Hypertensive
pregnant
women
197
BM-Test-5L vs
24-h protein
excretion
determined by
Benzethonium
Chloride assay
0.3g/24 h
70%
22
98
97
35
continued
37
Study
Population
Comparison
Cut-off
Number
of true
positives
88
Hypertensive
pregnant
women
197
BM-Test-5L vs
24-h protein
excretion
determined by
Bradford assay
0.3g/24 h
25%
57
97
87
87
83
Hypertensive
pregnant
women
150
Multistix-AMES
vs 24-h urine
protein (random
dipstick)
0.3g/l
84/150 =
56%
84
61
57
86
Multistix-AMES
0.3g/l
vs 24-h urine
protein (aliquot
collected at 6 hrs)
84/150 =
56%
84.5
90.1
84.5
90.0
70/230 =
30%
86
38
70/230 =
30%
46
88
NR
36
97
68
88
80
Hypertensive
pregnant
women
230
Sensitivity
(%)
Specificity
(%)
PPV (%)
NPV
(%)
81
Pregnant
women
690
Multistix 10SG
samples vs 24-h urine
protein
82
Hypertensive
pregnant
women
300
Urine dipstick
0.3g/24 h
samples (unspecified) vs
24-h urine protein
NR
67
74
92
34
84
Pregnant
women
103
NR
100
62
24
15 mg/dl
Studies in pregnant women showed that reagent strips had low sensitivity and variable
specificity for detecting proteinuria. The positive and negative predictive values also varied
greatly. (Level 1b +)
In people with kidney disease, a +1 or a +3 result on a reagent strip had high sensitivities to detect
a PCR 1 g protein/g creatinine (roughly >1 g/day), and the specificity was low.86 Another study
showed that reagent strips had low sensitivity for detecting proteinuria (>0.150 g/24 h).85
(Level 1b +)
38
4 Investigation of CKD
4.3.5
39
predominantly detect albumin, not total protein, but are not reliably quantitative. Studies to
inform intervention levels of ACR in non-diabetic CKD are not yet available and it is not
possible to derive a simple correction factor that allows the precise conversion of ACR values to
PCR. However, ACR has far greater sensitivity than PCR for the detection of low levels of
proteinuria and thus lends itself to detection and identification of CKD.
When the clinical and cost-effectiveness evidence is all taken into account, considerable
uncertainty remains about the choice of ACR or PCR. Clinical opinion was divided among
stakeholder organisations and within the GDG, but given the considerations above, the GDG
made a consensus recommendation that ACR should be the test of choice to identify
proteinuria and possible chronic kidney disease. The GDG however also noted that there will
often be good clinical reasons for subsequently using PCR to quantify and monitor significant
levels of proteinuria.
The GDG noted that an ACR of 30 mg/mmol, or PCR 50 mg/mmol in association with
haematuria or an ACR 70 mg/mmol, or PCR 100 mg/mmol in the absence of haematuria were
considered indications for referral to nephrology (see section 6.1.4). It was agreed that the finding
of levels of ACR <70 mg/mmol, or PCR <100 mg/mmol should be confirmed using an early
morning urine sample.
4.3.6
s
R10
Haematuria
When testing for the presence of haematuria, use reagent strips rather than urine microscopy.
G
Evaluate further if there is a result of 1+ or more.
G
Do not use urine microscopy to confirm a positive result.
40
RECOMMENDATIONS
Proteinuria
R11
Do not use reagent strips to identify proteinuria unless they are capable of specifically
measuring albumin at low concentrations and expressing the result as an ACR .
R12
To detect and identify proteinuria, use urine albumin:creatinine ratio (ACR) in preference, as
it has greater sensitivity than protein:creatinine ratio (PCR) for low levels of proteinuria. For
quantification and monitoring of proteinuria, PCR can be used as an alternative. ACR is the
recommended method for people with diabetes.
R13
For the initial detection of proteinuria, if the ACR is 30 mg/mmol or more (this is
approximately equivalent to PCR 50 mg/mmol or more, or a urinary protein excretion
0.5 g/24 h or more) and less than 70 mg/mmol (approximately equivalent to PCR less than
100 mg/mmol, or urinary protein excretion less than 1 g/24 h) this should be confirmed by
a subsequent early morning sample. If the initial ACR is 70 mg/mmol or more, or the
PCR 100 mg/mmol or more, a repeat sample need not be tested.
4 Investigation of CKD
4.4
4.4.1
Clinical introduction
Proteinuria is a cardinal sign of kidney disease. Measurement of total protein in urine is a
traditional, inexpensive and well established test for kidney injury. A vast body of nephrological
literature is predicated on 24-hour urinary total protein. Significant proteinuria is an independent
risk factor for both progression of CKD and cardiovascular disease. Monitoring of urinary
proteinuria is both part of the routine evaluation of those at risk of CKD and is an important
method of assessing progression and response to therapy.
Proteins normally excreted in the urine include albumin, low molecular weight immunoglobulin
(filtered plasma proteins), and secreted tubular proteins. There is no consistent definition of
proteinuria. The upper limit of normal is approximately 150 mg/24 h, equivalent to a
protein:creatinine ratio (PCR) of 15 mg/mmol (given an average daily urine creatinine excretion
of 10 mmol), but the cut off for abnormal varies from laboratory to laboratory. By contrast,
urinary albumin measurement provides a quantitative, relatively standardised measurement of
excretion of the single most important protein in most nephropathies. The normal mean value
for urine albumin is 10 mg/day, microalbuminuria is defined as 30300 mg/day or an
albumin:creatinine ratio (ACR) of >2.5 mg/mmol in men and >3.5 mg/mmol in women.
Macroalbuminuria is a urinary albumin greater than 300 mg/day (ACR >30 mg/mmol).
Proteinuria displays considerable biological variability, and may be increased by urinary tract
infection (UTI), upright posture, exercise, fever, and heart failure as well as by kidney disease.
Biological variation of both measures is high, with lower variation generally being reported for
an albumin:creatinine ratio (ACR) on an early morning urine (EMU) compared to PCR
(e.g. 36% versus 48% respectively). There is a high correlation between total protein and
albuminuria at high levels of protein excretion (so-called nephrotic range proteinuria, PCR
>300 mg/mmol) but at low levels correlation is poor. This is because urine protein
measurement in the normal range and at low levels is both imprecise and relatively nonspecific. Albumin as a proportion of total protein is highly variable at normal and moderately
increased levels of proteinuria.8992
The UK CKD Guidelines have defined proteinuria as a PCR of 45 mg/mmol or an ACR
30 mg/mmol but suggest that, in the absence of concomitant haematuria, this should not act
as a trigger for active intervention until the PCR exceeds 100 mg/mmol (ACR >70 mg/mmol).33
KDOQI guidelines define proteinuria as a PCR >23 mg/mmol (200 mg/g). The Welsh Renal
NSF has defined proteinuria as a PCR of 100 mg/mmol, approximately equivalent to an
excretion rate of 1000 mg/24 h.
It has been accepted for many years that total protein measurement is insufficiently sensitive to
detect the onset of diabetic nephropathy and that urine albumin must be used for this purpose.
This is enshrined in many clinical practice guidelines including those for type 1 and 2 diabetes
produced by NICE. There is also evidence that urine albumin is a more sensitive test to enable
detection of glomerular disease associated with some other systemic diseases (e.g. SLE, hypertension). The diabetic nephropathy literature and the classification of diabetic nephropathy is
based upon urine albumin excretion (commonly expressed as an ACR measurement) and the
41
recent Kidney Disease Improving Global Outcomes (KDIGO) classification of CKD is clear in
that it requires urine albumin measurement to facilitate diagnosis of stage 1 and 2 CKD. In
other words, the presence of low-level albuminuria (microalbuminuria) in an individual with
a glomerular filtration rate (GFR) 60 ml/min/1.73 m2 is indicative of CKD irrespective of
whether diabetes mellitus is present or not. There is strong evidence from epidemiological
studies linking urinary albumin excretion to cardiovascular mortality and kidney disease
progression in people with diabetes and to cardiovascular and non-cardiovascular mortality in
those without diabetes.9396 Amongst people with diabetes, microalbuminuria is used as a
therapeutic target that can be modified by renin-angiotensin-aldosterone system blockade with
resulting improvement in clinical outcomes; there is currently a poor evidence base for this
strategy in non-diabetic kidney disease.97
In the most common types of CKD (i.e. that due to diabetes, hypertension and glomerular
disease) and in kidney transplant recipients, albumin is both the most abundant protein in urine
and a more sensitive marker of disease. The NKF-KDOQI guidelines therefore recommend
urinary albumin measurement in preference to total protein when detecting and monitoring
proteinuria. Conversely, the UK CKD guidelines and CARI guidelines have recommended urine
PCR for non-diabetic kidney disease, with ACR being reserved for patients with diabetes.33 The
Welsh Renal NSF has adopted a similar position and this was endorsed by the UK consensus
conference statement and by the Scottish Intercollegiate Guidelines Network.34
There is a need to reconcile these approaches. Increasingly the management of CKD is being
undertaken by general practitioners and other non-nephrologists. Also, where the National
Vascular Screening Programme identifies people with conditions such as hypertension, diabetes
and impaired GFR an ACR will be recommended. Furthermore, the Quality and Outcomes
framework now includes proteinuria in the CKD indicators. There is a need for consistency
between detection of proteinuria in diabetes and detection of proteinuria in CKD. The current
dual system of proteinuria/albuminuria reporting is at the least confusing and to patients
probably unfathomable. Problems remain in defining conversion factors that would enable the
proteinuria evidence base to be interpreted on the basis of urine albumin results. This is
particularly true at lower levels of protein excretion, where the contribution of albumin to total
protein is more variable. To attempt to address this, a call for evidence1 was circulated to
registered stakeholder organisations specifically seeking evidence relating to the equivalence of
ACR to PCR and to 24-hour urinary protein excretion.
Clinical question: What are the benefits in terms of accuracy and cost in measuring
albumin:creatinine ratio versus protein:creatinine ratio to quantify proteinuria in adults
with CKD?
Call for evidence: What is the equivalence between urinary albumin:creatinine ratios and
24-hour urinary protein excretion and urinary protein:creatinine ratio?
4.4.2
Methodology
There were no studies that directly compared protein:creatinine ratio (PCR) with
albumin:creatinine ratio (ACR) and provided sensitivity and specificity outcomes. Instead,
studies were selected that compared ACR or PCR to the reference standard test, timed overnight
42
4 Investigation of CKD
or 24-hour urinary albumin (or protein) excretion. Studies were excluded if the sample size was
small (lower than 100) or if the sulfosalicylic acid test, protein heat coagulation test, or urine
electrophoresis were used as the reference test.
Two studies compared PCR in a spot urine sample to timed urinary 24-hour protein excretion in
diabetic adults98 or in non-diabetic adults with proteinuria and CKD.99 These two studies only
reported the correlation between the reference standard and PCR. Six studies compared the ACR
in a spot urine sample to timed overnight or 24-hour urinary albumin excretion in diabetic
adults,100103 in a Dutch general population,104 and in a South Asian general population in
Pakistan.105 Sample sizes in the eight studies ranged from 109 to 2527.
4.4.3
43
4.4.4
s
Evidence statements
Correlation of PCR and 24-hour urinary protein
In diabetic and non-diabetic populations (N=229 and N=177, respectively), spot morning PCR
and 24-hour urinary protein excretion rates were log-transformed and a linear regression was
fitted, which was highly significant (=0.948, p<0.0001 in people without diabetes, and =0.9,
significance not stated for people with diabetes).98,99 However, PCR becomes a less accurate
predictor of 24-hour urinary protein excretion in the higher values. (Level 1b +)
44
4 Investigation of CKD
4.4.5
s
Sensitivity and specificity of ACR or PCR compared with 24-hour protein excretion
To predict a 24-hour urine protein >1 g/day (N=1739, the subgroup in whom 24-hour protein
had been successfully collected), a PCR threshold of 98 mg/mmol was found to give sensitivity
of 0.95 with specificity of 0.83. An ACR threshold of 16.5 mg/mmol was found to give the same
0.95 sensitivity, this time with specificity of 0.7. Similarly, to predict a 24-hour urine protein
>450 mg/day, a PCR threshold of 45 mg/mmol had the desired sensitivity of 0.95 and specificity
of 0.83, whereas the ACR threshold of 9.5 mg/mmol achieved the same sensitivity with
specificity of 0.77. Confidence intervals are not given for these estimates, and it is not possible
to construct them from the details available.108 (Level 1b +)
45
4.4.6
46
4 Investigation of CKD
Table 4.5 Urine protein: ACR, PCR and 24-hour protein excretion
Albumin:creatinine ratio
Protein:creatinine ratio
24-hour urinary
protein excretion (g/day)
30 mg/mmol
70 mg/mmol
4.4.7
RECOMMENDATIONS
R14
In people without diabetes consider clinically significant proteinuria to be present when the ACR
is 30 mg/mmol or more (this is approximately equivalent to PCR 50 mg/mmol or more, or a
urinary protein excretion 0.5 g/24 h or more).
R15
In people with diabetes consider microalbuminuria (ACR more than 2.5 mg/mmol in men
and ACR more than 3.5 mg/mmol in women) to be clinically significant.
R16
All people with diabetes, and people without diabetes with a GFR less than 60 ml/min/
1.73 m2, should have their urinary albumin/protein excretion quantified. The first abnormal
result should be confirmed on an early morning sample (if not previously obtained).
R17
Quantify by laboratory testing the urinary albumin/protein excretion of people with an eGFR
60 ml/min/1.73 m2 or more if there is a strong suspicion of CKD (see also 4.2.7).
4.5
4.5.1
Clinical introduction
Ultrasound is the first-line imaging study for evaluating people with previously undiagnosed
kidney disease. It helps the clinician separate end stage kidney disease from potentially
reversible acute kidney injury or earlier stages of CKD by:
G
determining the presence, size and shape of kidneys and assessing cortical thickness prior
to renal biopsy
G
identifying obstructive uropathy
G
assessing renal scarring
G
identifying polycystic kidney disease.111
Although ultrasound is the optimal imaging modality for CKD, it is not known what
proportion of those with CKD will benefit from ultrasound imaging.
I
4.5.2
What are the indications for renal ultrasound in adults with CKD?
Methodology
Due to the difficulty in searching this question, the results of a broad literature search were
reviewed for systematic reviews on criteria for referral for renal ultrasound in a CKD
population. No studies were identified. An algorithm was provided by a GDG member, who
47
4.5.3
4.5.4
Evidence statements
There were no clinical papers found to review.
4.5.5
48
4.5.6
RECOMMENDATIONS
R18
4 Investigation of CKD
G
G
G
G
R19
Advise people with a family history of inherited kidney disease about the implications of an
abnormal result before a renal ultrasound scan is arranged for them.
49
5.1.1
Clinical introduction
If we cannot prevent CKD then we want to minimise the associated adverse outcomes. To do
this we need to know:
G
what the adverse outcomes are
G
at what level of GFR we should be alert to adverse outcomes and
G
the impact of associated factors such as age, gender and presence or absence of
proteinuria at any given level of GFR.
Large population studies have clearly suggested that the risk of death, hospitalisation and
cardiovascular events rises exponentially at levels of GFR below 60 ml/min/1.73 m2.13 Other
complications associated with reduced GFR, such as the increased potential for dose-related
drug toxicity, are less obvious but equally important.
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI)
stratified chronic kidney disease into five stages according to glomerular filtration rate and the
presence of kidney damage:
G
Stage 1: GFR >90 ml/min/1.73 m2 with other evidence of kidney damage (persistent
microalbuminuria, persistent proteinuria, persistent haematuria, structural abnormalities
of the kidneys demonstrated on ultrasound scanning or other radiological tests, or
biopsy-proven chronic glomerulonephritis)
G
Stage 2: GFR 6089 ml/min/1.73 m2 with other evidence of kidney damage
G
Stage 3: GFR 3059 ml/min/1.73 m2
G
Stage 4: GFR 1529 ml/min/1.73 m2
G
Stage 5: GFR <15 ml/min/1.73 m2.
CKD is common and its prevalence increases markedly with age, with a female predominance.
However, the CKD classification is neither staged according to age and gender, nor according to
level of proteinuria. All patients, regardless of age, gender and proteinuria or albuminuria are
considered to have at least moderately severe CKD when their GFR is <60 ml/min/1.73 m2.
However, we have some evidence that GFR reduces as a consequence of ageing,112 although the
exact level of reduction is still a subject of debate, and reduced GFR is very common in certain
older populations.113 It has been suggested that the rate of progression of CKD in black and
minority ethnic groups may be higher than in Caucasians.24 The ABLE projects in the UK have
also suggested that kidney disease in people of South Asian and African-Caribbean ethnicity
may deteriorate more rapidly to established renal failure25. Long term, the ABLE study aims to
identify the reasons for this faster deterioration.
The degree of proteinuria is a significant risk factor both for progression of CKD and for
cardiovascular disease.114117 We therefore need a better understanding of the prognostic
significance of different levels of GFR, and of what other factors should be considered. Intuitively
51
a one size fits all approach to clinical decision making throughout the population is unlikely to
be appropriate. This has already been recognised by the CARI (Caring for Australasians with
Renal Impairment) guidelines which recommend that the suffix (p) should be applied to the
corresponding CKD stage for all patients with proteinuria 1 g/day. The recently published SIGN
(Scottish Intercollegiate Guidelines Network) guideline also makes the same recommendation, as
did the UK consensus conference on early CKD which also recommended sub-classifying CKD
stage 3 into 2 groups: 3A which defines a lower risk group with GFR 4559 ml/min/1.73 m2, and
3B which defines a higher risk group with GFR 3044 ml/min/1.73 m2.34
5.1.2
At what level of GFR are patient outcomes significantly affected? Does this change with
age? Gender? Ethnicity? Presence or absence of proteinuria?
Methodology
Twenty-two longitudinal studies assessed the risks of all-cause mortality, cardiovascular disease,
hospitalisation, renal disease progression, and the quality of life of adults with decreasing eGFR
levels. Baseline characteristics were significantly different between groups with lower eGFR
compared with higher eGFR. People with low eGFR were almost always older, more likely to be
female, and had higher prevalence of diabetes and cardiovascular diseases. While statistical
analyses in these studies have been adjusted for confounding variables such as age, gender, race,
and several comorbidities, it is difficult to identify all variables which could potentially affect the
size of the risk. These unknown variables make it impossible to assign cause and effect, and the
confidence intervals were sometimes so wide that the associations with eGFR could be spurious.
Eight cohort studies examined the association between different eGFR levels and several outcomes
of interest in populations with concomitant cardiovascular disease; specifically high-risk
hypertension,118 acute myocardial infarction,119,120 heart failure,121 acute coronary syndrome,122
coronary disease,123 coronary artery disease124 and peripheral arterial disease.125 These studies
ranged in sample size from 1015 to 31,897 and length of follow-up ranged from 1 to 6 years. The
mean age of people with higher eGFR (typically >60 ml/min/1.73 m2) ranged from 57 to 72 years,
while the mean age range of those with lower eGFR (typically <60 ml/min/1.73 m2) ranged from
62 to 83 years. The study by Beddhu et al. was excluded due to missing patient baseline data, and
lack of inclusion and exclusion criteria.
A very large US cohort study (N=1,120,295, follow-up 2.8 years, age range 4771) examined
age-adjusted risk of mortality, cardiovascular events, and hospitalisation in people with stage 3,
4, or 5 CKD compared to people with GFR >60 ml/min/1.73 m2.13 In another US cohort study,
participants with CKD were age- and sex-matched with people without CKD (N=19,945 pairs,
follow-up 4.5 years) and the risk of all-cause mortality was examined.126 The KEEP study
assessed mortality and cardiovascular disease (N=37,153, median follow-up 16 months) in a
self-selected population of people with diabetes, hypertension, or a family history of kidney
disease, hypertension, or diabetes.127 Participants in the ARIC cohort (N=14,280) were assessed
for incidence of peripheral arterial disease as a function of eGFR.128
A UK cohort study (N=3249 unreferred, 2.6 years follow-up, mean age 82 years) examined the
mortality outcomes of people who had not been referred to renal services with stage 4 or 5 CKD
compared to eGFR 3042 ml/min/1.73 m2.11
Three cohort studies in diabetic adults examined the association of eGFR with renal disease
progression and cardiovascular outcomes.129131 A UK study of people identified from a
52
diabetes register (N=3288, median follow-up 10.5 years) assessed all-cause mortality and
mortality due to circulatory disease, ischaemic heart disease, or cerebrovascular disease in this
population stratified by eGFR.131 The Patel et al. study (N=12,570, follow-up 3 years, range of
groups mean ages 6472) reported mortality rates and kidney disease progression rates at
different eGFR levels in a predominantly male diabetic cohort. This study was rejected as there
was little statistical analysis of the results; only mortality rates were presented.
Quality of life outcomes such as cognitive impairment, frailty, and disability were assessed in
postmenopausal women124 or in older populations with varying levels of serum creatinine132
or eGFR.133
The effect of proteinuria or no proteinuria at a particular eGFR on the risk of ESRD was
assessed in a Japanese population study (N=95,255, follow-up 7 years).134 The So et al. study
investigated the effect of proteinuria on patient outcomes within several GFR ranges in a
Chinese diabetic cohort (N=4421, follow-up 3.3 years, mean ages in higher versus lower eGFR
ranges 57 and 69 years).
The effects of age and gender on mortality and kidney disease progression were examined in
people with stage 3 CKD in a Norwegian population study (N=3027, median observation time
3.7 years, median age 75 years).135 In a predominantly male cohort study (N=8,218,817, mean
follow-up 3.17 years), people were stratified by age within decreasing ranges of eGFR and the
effect of age on mortality was examined.136 In another analysis of this cohort (N=209,622,
follow-up 4 years), people were stratified by eGFR and the risk of death or progression to ESRD
was assessed with increasing age.137
There were no studies that assessed cardiovascular and renal outcomes as a function of race
within different levels of renal function.
Table 5.1 summarises the association of GFR and mortality, cardiovascular risk, and renal
disease progression in adults with varying severity of CKD.
5.1.3
5.1.4
s
Evidence statements
All-cause mortality
Three studies showed that the risk of all-cause mortality rose sharply in people with eGFR
<45 ml/min/1.73m2.13,119,121 Every 10 ml/min/1.73 m2 decrease in GFR from 75 ml/min/
1.73 m2 was associated with a significantly higher risk of all-cause mortality (adjusted HR 1.09,
95% CI 1.061.14, p<0.001).121 (Level 2+)
Cardiovascular mortality
Three studies showed that risk of cardiovascular mortality increased with declining renal
function.119,121,131 The risk of circulatory disease mortality, ischaemic heart disease mortality, and
cerebrovascular disease mortality all significantly increased with decreasing renal function.131
(Level 2+)
53
Cardiovascular events
Three studies showed NS risk of cardiovascular events in people with GFR 6089 ml/min/
1.73 m2 compared with eGFR >90 ml/min/1.73 m2.119,127,130 The risk of cardiovascular events
significantly increased at eGFR <60 ml/min/1.73 m2.118,119,127,128 The risk of cardiovascular
events rose sharply in people with eGFR <45 ml/min/1.73m2.13 (Level 2+)
Frailty
People with chronic renal insufficiency (CRI) (N=648) had a significantly increased risk of
frailty (adjusted odds ratio (OR) 1.76, 95% CI 1.282.41, p not stated) compared to people
without CRI. The prevalence of frailty increased with decreasing GFR (p for trend <0.001) and
was particularly high in those with GFR <40 ml/min/1.73 m2. Black ethnicity and female
gender were associated with increased likelihood of frailty.132 (Level 3)
Disability
There was NS risk of disability for people with CRI compared to people without CRI. Black race
and female gender were associated with increased likelihood of disability.132 (Level 3)
54
55
1.073.18, p=0.03). Similarly, people with GFR 6089 ml/min/1.73 m2 with albuminuria had a
significantly increased risk of cardiovascular events than those without albuminuria (HR 1.89,
95% CI 1.133.16, p=0.016).130 (Level 2+ and 3)
Population
Reference
GFR (ml/min/
1.73 m2)
GFR
8975
(95% CI)
GFR
74.960
(95% CI)
GFR
5945
(95% CI)
GFR
4530
(95% CI)
GFR
2915
(95% CI)
GFR <15
(95% CI)
Men with
60
peripheral
vascular disease
(N=5787)
121
Heart failure
(N=2680)
>90
NS
NS
1.50 (1.12,
2.00),
p=0.006
122
Acute coronary
syndrome
(N=5549)
>80
119
Acute MI and
LVEF 40%
(N=2183)
75
NS
130
Type 2 diabetes 90
(N=4421)
NS
13
Kaiser
Permanente
cohort
(N= 1120295)
126
Kaiser
6089
Permanente
cohort (N=19945
sex, age
matched pairs)
60
NS
9.82 (4.53,
21.0)
1.2 (1.1,
1.2)
3.2
(3.13.4)
5.9
(5.46.5)
Matched RR 1.311
(1.142, 1.505),
p<0.0001
Matched
RR 3.335
(2.272,
4.896),
p<0.0001
1.8
(1.71.9)
continued
56
Population
Reference
GFR (ml/min/
1.73 m2)
GFR
8975
(95% CI)
GFR
74.960
(95% CI)
GFR
5945
(95% CI)
GFR
4530
(95% CI)
GFR
2915
(95% CI)
GFR <15
(95% CI)
3042.8
1.41 (1.25,
1.60),
p<0.001
3.12 (2.53,
3.83),
p<0.001
11
People
unreferred to
renal services
(N=3822)
127
Adults with
90
diabetes,
hypertension, or
family history of
diabetes,
hypertension,
or kidney disease
(N=37153)
NS
NS
NS
131
Adults with
type 1 + type 2
diabetes
(N=3288)
90
Heart failure
(N=2680)
> 90
NS
NS
1.54 (1.22,
1.94),
p<0.001
119
Acute MI and
LVEF 40%
(N=2183)
75
NS
NS
Hypertension +
high risk for
CVD (N=31897,
ALL-HAT)
90
119
Acute MI and
LVEF 40%
(N=2183)
75
130
Type 2 diabetes 90
(N=4421)
NS
13
Kaiser
Permanente
cohort
(N=1120295)
60
Recurrent
MI: NS
heart failure:
NS
NS
1.4
(1.41.5)
2.0
(1.92.1)
3.23 (1.74,
5.99)
2.8
(2.62.9)
3.4
(3.13.8)
continued
57
127
Population
Reference
GFR (ml/min/
1.73 m2)
Adults with
90
diabetes,
hypertension, or
family history of
diabetes,
hypertension, or
kidney disease
(N=37153)
GFR
8975
(95% CI)
GFR
74.960
(95% CI)
NS
GFR
5945
(95% CI)
GFR
4530
(95% CI)
GFR
2915
(95% CI)
NS
1.1
(1.11.1)
2.1
(2.02.2)
GFR <15
(95% CI)
Kaiser
Permanente
cohort
(N=1120295)
60
1.5
(1.51.5)
3.1
(3.13.3)
Hypertension + 90
high risk for CVD
(N=31897,
ALL-HAT)
130
Type 2 diabetes 90
(N=4421)
NS
27.3
(15.6, 47.8)
NS
ARIC cohort
(N=14280)
90
5.1.5
58
The GDG noted that although it has been suggested that the rate of progression of CKD in black
and ethnic minority groups may be higher than in Caucasians, as yet there is no published
evidence to support this.
It was noted that the presence of proteinuria was associated with a doubling of CVD risk and
mortality at all levels of GFR. This led to the proposal to adopt the suffix (p) notation to
denote the presence of proteinuria when staging CKD. Evidence from longitudinal population
studies and from meta-analysis of progression risk and level of proteinuria suggested that an
ACR 30 mg/mmol should be used as a marker of the increased risk (roughly equivalent to a
PCR 50 mg/mmol or proteinuria values 0.5 g/day).
The GDG agreed not to recommend age-related decision points for eGFR. However, it seemed
clear that in people aged >70 years, an eGFR in the range 4559 ml/min/1.73m2, if stable over
time and without any other evidence of kidney damage is unlikely to be associated with CKDrelated complications.
5.1.6
RECOMMENDATIONS
R20
Use the suffix (p) to denote the presence of proteinuria when staging CKD.
R21
For the purposes of this classification define proteinuria as urinary albumin:creatinine ratio
(ACR) 30 mg/mmol or PCR 50 mg/mmol (approximately equivalent to urinary protein
excretion 0.5 g/24 hours)
R22
R23
At any given stage of CKD, management should not be influenced solely by age.*
Stages of chronic kidney disease (updated)
Stagea
GFR
(ml/min/1.73 m2)
Description
90
6089
3A
4559
3B
3044
1529
<15
Use the suffix (p) to denote the presence of proteinuria when staging CKD (recommendation R20).
In people aged >70 years, an eGFR in the range 4559 ml/min/1.73m2, if stable over time and without any
other evidence of kidney damage, is unlikely to be associated with CKD-related complications.
59
5.2
5.2.1
Clinical Introduction
The early identification and treatment of CKD is essential to decrease the risk of cardiovascular
disease, progression to ESRD, and mortality. Identification of high-risk groups can help clinicians
monitor renal function and identify people with CKD at an earlier disease stage. Although general
population screening may not be cost-effective, targeted screening directed at subgroups of the
population who might derive the most benefit from CKD detection was shown to be an effective
strategy.138 A national programme to identify vulnerability to vascular diseases was announced
by the Health Secretary in April 2008, following initial results from modelling work carried out
by the Department of Health. This work suggested that a vascular check programme would
prevent 4000 people a year from developing diabetes and could also detect at least 25,000 cases of
diabetes or kidney disease earlier. In those conditions where the prevalence of CKD is high and
the risks of preventable complications are increased, testing for CKD is clearly warranted. The
KEEP programme identified people with diabetes and hypertension, or people with a first-line
relative (parent, grandparent, brother or sister) with diabetes, high blood pressure or kidney
disease as being at high risk of CKD. Are there additional high-risk people who should be tested
for CKD? The UK CKD guidelines also included those with a high risk of obstructive uropathy,
all forms of CVD, multisystem diseases with the potential to involve the kidney such as SLE, and
conditions requiring long-term treatment with potentially nephrotoxic drugs.33 In addressing
this question all of these factors were considered, together with other lifestyle factors such as
smoking, obesity and alcohol intake.
I
5.2.2
Methodology
Three cohort and sixteen observational or cross-sectional studies examined several risk factors for
developing CKD. Table 5.2 summarises the risk factors associated with development of CKD.
Age
The association between developing CKD and age was examined in cross-sectional studies
conducted in the UK,10 Norway,139,140 USA20,22 and Australia.141
Gender
The association between developing CKD and gender was examined in cross-sectional studies
conducted in the UK,10 Norway,140 USA20 and Australia.141 A longitudinal study examined the
association between age and death due to CKD or need for dialysis in an American cohort
(N=23,534, 20-year follow-up).142 This study, while large, was limited by no assessment of renal
disease at baseline, and poor identification of diabetes (assessed by medication use in medical
records).
Hypertension
The association between hypertension and risk of developing CKD was examined in one
longitudinal study142 and cross-sectional studies conducted in Norway,140 USA,20 and
Australia.141
60
Diabetes
The association between diabetes and risk of developing CKD was examined in one longitudinal
study142 and cross-sectional studies conducted in the UK,143 Norway,140 USA20 and Australia.141
Heredity
The prevalence of nephropathy or ESRD in diabetic siblings of people with diabetic nephropathy
was compared with diabetic siblings of people without diabetic nephropathy.149,150
The incidence of a family history of ESRD among 28,111 ESRD patients initiating renal
replacement therapy during 1994,151 or during 1995 and 2003152 was examined. A family
history of ESRD was considered present if an incident ESRD patient reported having either a
first-degree (parent, child, sibling) or second-degree (grandparent, aunt, uncle, grandchild, or
half-sibling) relative with ESRD.
Ethnicity
The incidence of microalbuminuria was compared between European, South Asian, and
African-Caribbean people (N=2965) in the UK. This cohort study was excluded as 27% of the
cohort did not have albumin excretion rate measurements and there were significant differences
between those whose data were included and those whose data were not. The study mainly
assessed the relationship between microalbuminuria and coronary heart disease, rather than
ethnicity and the development of CKD.153
61
One case series study (UK Prospective Diabetes Study (UKPDS) 74)154 investigated the
associations of ethnicity with the development of microalbuminuria, macroalbuminuria, and
CrCl 60 ml/min/1.73 m2 in adults with newly diagnosed type 2 diabetes (N=5032, 15 years
median follow-up). This study should be interpreted with caution as the multivariate analysis
was restricted to N=2167, a loss of half of the study participants.
In the NHANES III study, prevalence of severe or moderate CKD was compared between nonHispanic black people (N=4163) and non-Hispanic white people (N=6635).20
Smoking
One case series (UKPDS 74)154 investigated the associations of smoking with the development
of microalbuminuria or CrCl 60 ml/min/1.73 m2 in adults with newly diagnosed type 2
diabetes (N=5032, 15 years median follow-up). Two US longitudinal studies examined the
association between smoking and death due to CKD or development of ESRD.142,145
Alcohol consumption
A longitudinal study followed 9082 Americans for 13 years and analysed the effect of alcohol
consumption on the risk of death due to CKD or ESRD.145
Physical inactivity
A longitudinal study followed 9082 Americans for 13 years and analysed the effect of physical
inactivity on the risk of death due to CKD or ESRD.145
Socioeconomic deprivation
The association between developing CKD and socioeconomic deprivation (measured with a
Townsend score) was examined in a UK cross-sectional study.10
5.2.3
62
5.2.4
s
Evidence statements
Age as a risk factor for developing CKD
Four cross-sectional studies showed that older people (over 65 years of age) had a greater risk
of an eGFR <60 ml/min/1.73 m2 than younger people.10,20,140,141 Analysis of a Norwegian
cross-sectional study showed that screening people with diabetes or hypertension or people
over 55 years of age identified 93% of cases with stage 3-5 CKD (number needed to screen
(NNS) 8.7, 95% CI 8.59.0).139 (Level 3)
Body mass index or metabolic syndrome as risk factors for developing CKD
The risk of developing CKD (GFR <60 ml/min/1.73 m2) increased with increasing BMI
(p=0.007). Compared to men who remained within 5% of their baseline BMI (N=5670), men
who had a >10% increase in BMI (N=1669) had a significantly increased risk of CKD (OR 1.24,
95% CI 1.031.50).144 (Level 2+)
By contrast, the NHANES II follow-up study showed NS risk for a CKD-related death or ESRD
at any level of BMI.145 (Level 3)
Metabolic syndrome was significantly associated with an increased risk of developing CKD. As
the number of traits increased, there was a significant stepwise increase in risk of developing
CKD. Those with 5 criteria had an OR of 2.45 (95% CI 1.324.54) for developing CKD
compared to those with none.146 (Level 2+)
63
64
Population
Definition of CKD
146
10,096
148
12,728
147
13,826
continued
65
Population
Definition of CKD
144
Physicians Health
Study cohort, USA
11,104
145
Follow-up of
NHANES II, USA
9,082
10
Cross-sectional
Southampton and
South-west
Hampshire, UK
404,541
143
Cross-sectional;
162,113
Surrey, Kent,
greater Manchester
area, UK
continued
66
Population
Definition of CKD
141
Cross-sectional,
Australia
11,247
20
Cross-sectional
NHANES III, USA
15,600
continued
67
Population
Definition of CKD
140
Cross-sectional,
Norway HUNT II
65,181
142
Case series,
CLUE study
23,534
154
Case series,
type 2 diabetics,
UKPDS
2,167
Development of
microalbuminuria
(UAC 50299 mg/l)
Development of
macroalbuminuria (UAC
300 mg/l)
CrCl 60 ml/min/1.73 m2
DBP = diastolic blood pressure; Lp = lipoprotein; SBPB = systolic blood pressure; UAC = urinary albumin concentration
68
5.2.5
Most hypertensive patients are already on low dose ACEI. The difference in effects
between high and low dose ACEI is not clear but the effectiveness of screening might be
over-estimated for such patients.
In the base case analysis, ACR is assumed to be 100% sensitive and 100% specific. Even in
the sensitivity analysis, the model doesnt measure the health impact or long-term costs of
false positives.
Benefits of early diagnosis other than from ACEI/ARB treatment are not captured by the
model.
5.2.6
70
disease, chronic heart failure, peripheral vascular disease and cerebrovascular disease are all risk
factors for CKD. The GDG noted that the increased prevalence of CKD seen in the NHANES
studies (19881994 compared with 19992004) was associated with an increased prevalence of
diagnosed diabetes and hypertension.
The cost-effectiveness evidence suggests that testing for CKD in high-risk groups (such as those
with hypertension or diabetes) is highly cost-effective. However, for over 55s without additional
risk factors, the prevalence of CKD with proteinuria was too low for testing to be cost-effective.
Although specific evidence for drug-induced nephrotoxicity was not considered, the GDG
noted that both acute and chronic use of drugs known to be potentially nephrotoxic can lead
to CKD. The use of certain agents such as lithium and calcineurin inhibitors should be
monitored and the GDG considered that long-term chronic use of NSAIDs should prompt an
annual GFR check. Further information can be obtained in the BNF.
The GDG did not consider the evidence about smoking, alcohol intake, abnormal lipids,
obesity (in the absence of metabolic syndrome), lower socioeconomic status and ethnicity
strong enough to recommend that people in these groups should be tested for CKD.
There was uncertainly regarding the significance of a family history of CKD but the GDG
recommended that people with a family history of stage 5 CKD or hereditary kidney disease
should be considered at risk of having CKD.
GDG consensus was that those with structural renal tract disease, multiple and recurrent renal
calculi and urinary outflow tract obstruction should be considered at risk of having CKD. The
GDG also recommended that people found incidentally to have haematuria or proteinuria on
opportunistic medical testing should be considered at risk of having CKD.
5.2.7
RECOMMENDATIONS
R24
R25
Offer people testing for CKD if they have any of the following risk factors:
G
diabetes
G
hypertension
G
cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular
disease and cerebral vascular disease)
G
structural renal tract disease, renal calculi or prostatic hypertrophy
G
multisystem diseases with potential kidney involvement, e.g. systemic lupus
erythematosus (SLE)
G
family history of stage 5 CKD or hereditary kidney disease
G
opportunistic detection of haematuria or proteinuria.
R26
In the absence of the above risk factors, do not use age, gender, or ethnicity as risk markers to
test people for CKD. In the absence of metabolic syndrome, diabetes or hypertension, do not
use obesity alone as a risk marker to test people for CKD.
71
Defining progression
6.1.1
Clinical introduction
The Renal NSF adopted the US National Kidney Foundation Kidney Disease Outcomes Quality
Initiative (NKF-KDOQI) classification of CKD.35 Whilst the beauty of this classification is its
simplicity, this is also its weakness. The clinical features and course of CKD are dependent on a
number of factors including the underlying cause, severity and associated conditions of the
underlying cause.
Although the classification of CKD into 5 stages has been widely adopted, it has been criticised
as not being sufficiently sophisticated for clinical needs. The existing classification is neither
staged according to age, nor according to level of proteinuria. All patients, regardless of age,
gender and proteinuria/albuminuria are considered to have at least moderately severe CKD
when their GFR is <60 ml/min/1.73 m2. This guideline recommends that stage 3 should be
subdivided into 3A and 3B, and that the suffix (p) in parenthesis be adopted in the different
stages to underline the importance of proteinuria/albuminuria as an independent risk factor for
adverse outcomes (Table 6.1).
Table 6.1 Modifications to existing stages of chronic kidney disease
Stage
Description
GFR
(ml/min/1.73m2)
90
6089
3A
3B
4559
3044
1529
Kidney failure
Proteinuria
CKD is defined as either kidney damage (proteinuria, haematuria or anatomical abnormality) or GFR <60 ml/min/1.73 m2
present on at least 2 occasions for 90 days.
A further criticism of the existing classification of CKD has been the suggestion that loss of GFR
is a feature of ageing and that many people classified as stage 3 CKD are merely exhibiting a
normal ageing process. The effects of normal ageing on renal function are controversial. Data
from some studies suggest that the decline in GFR with increasing age may be largely attributable
to comorbidities such as hypertension and heart failure. Loss of renal function may not, therefore,
be an inevitable consequence of ageing.158160 This was supported by studies demonstrating no
or very little decline in GFR in the older population with longitudinal follow-up.161
73
The focus of defining progression of CKD in this section was to consider what constitutes
progression in terms of rate of decline of GFR in order to provide clear guidance to clinicians.
However, controversy over what constitutes normality in the group with the highest prevalence
of CKD makes defining what constitutes progression even more difficult. Consideration must
also be given to the inherent biological and analytical variation associated with estimation of
GFR from serum creatinine measurements.
I
6.1.2
Methodology
Decline in eGFR in the Prevention of Renal and Vascular Endstage Disease (PREVEND) cohort
(N=8592) was compared with the eGFR decline in people with macroalbuminuria (300 mg/24 h,
N=134) or impaired renal function (lowest 5% of the cohort in terms of CrCl or MDRD eGFR,
N=103). The power of this study was undermined by a high drop-out rate in the macroalbuminuria, impaired renal function, and haematuria groups, although the authors noted that
the baseline characteristics of those who were lost to follow-up were NS different from subjects
who completed follow-up.162
Two cross-sectional studies examined GFR decline in healthy kidney donors with increasing
age. GFR was measured by iothalamate clearance in 365 potential living kidney donors163 or by
inulin clearance in 141 healthy subjects who had a nephrectomy.164 The main limitation of the
Rule et al. study163 was that 71% of the kidney donors were related to recipients, therefore the
donors may have had a greater prevalence of subclinical renal disease. This was evident in the
lower GFR values in apparently healthy people (mean GFR=111 ml/min/1.73 m2 in healthy
twenty-year olds). As this was a retrospective analysis of medical records, there was no detail on
how often GFR was measured. The Slack et al. study164 did not address whether the donors
were relatives of the kidney recipients and there was no data from people >67 years of age.
The cross-sectional Biomedical Nijmegen Study measured eGFR (MDRD) in apparently
healthy men and women (N=3732) and in men and women with comorbid conditions
(N=2365). Limitations of this study included:
G
a questionnaire, rather than a clinical examination, was used to assess the health of
participants
G
GFR was estimated with the MDRD equation and creatinine was measured only once
G
the GFR decline was inferred from cross-sectional data, rather than from a longitudinal
follow-up.165
A cross-sectional study examined inulin clearance in healthy younger subjects (N=24, mean age
26 years) compared with healthy older people (N=29, mean age 68 years), hypertensive older
people (N=25, mean age 70 years) or older people with heart failure (N=14, mean age 69 years).
The younger and older healthy subjects were matched for body weight. This study was limited
by the small sample size and it did not address rate of GFR decline.159
Two observational studies from the Baltimore Longitudinal Study of Aging examined creatinine
clearance over time (19581981) in a male cohort aged 2297 years. In the first study,166 the
decline in creatinine clearance with increasing age was assessed in healthy males (N=548). In a
follow-up study,158 the decline in creatinine clearance over time in healthy males (N=254) was
compared with creatinine clearance decline in men with renal/urinary tract disease (N=118) or
74
6.1.3
6.1.4
s
Evidence statements
Renal functional decline in healthy adults
Two cross-sectional studies of healthy kidney donors showed that GFR declined with increasing
age and this was a steady decline as age increased. Regression analysis of GFR normalised to
body surface area was significant for age (p<0.001), but not sex (p=0.826).163,164 (Level 3)
In the Longitudinal Study of Aging male cohort, creatinine clearance was stable in healthy men
<35 years old, but then declined steadily in healthy men age 3560 years. After age 60, creatinine
clearance declined steeply.158,166 (Level 3)
Mean inulin clearance was significantly lower in older healthy people compared with young
healthy people.159 (Level 3)
In the Nijmegen Biomedical cross-sectional study, a GFR <60 ml/min/1.73 m2 was within the
normal reference range for non-diseased men >55 years old and non-diseased women >40 years
old (5th percentile).165 (Level 3)
Population
GFR decline
163
205
0.71 ml/min/year
163
160
0.46 ml/min/year
163
365
0.49 ml/min/1.73m2/year
164
141
0.4 ml/min/year
166
548
166
293
165
158
446
158
254
158
118
158
74
162
162
3,732
0.4 ml/min/year
6,894
86
162
68
161
Not stated
161
Not stated
161
Not stated
161
Not stated
76
6.1.5
6.1.6
RECOMMENDATIONS
R27
77
6.2
6.2.1
Clinical introduction
In the literature, progression of kidney disease has been variously defined as doubling of serum
creatinine, declining GFR or creatinine clearance, increasing proteinuria/albuminuria, and
progression to renal replacement therapy (RRT, dialysis or kidney transplantation) or end stage
renal disease. The list of possible factors associated with progression does not consider how
differences in access to healthcare and poverty may influence the initiation and progression of
CKD. Specifically, neither early life influences governing foetal development and low birth
weight nor childhood factors contributing to the emergence of hypertension and diabetes are
considered here.167169
Whilst it is clear that CKD is common, and recently published studies suggest that its prevalence
is increasing,22 it is also clear that many people with diagnosed CKD do not progress.11,12
Importantly, their risk of cardiovascular disease is massively increased compared to the general
population. In those that do progress, the subsequent mortality and morbidity risks rise
exponentially, as do the associated healthcare costs. A reduced GFR is also associated with a
wide range of complications such as hypertension, anaemia, renal bone disease, malnutrition,
neuropathy and reduced quality of life. It is therefore important to clarify exactly what factors
are associated with CKD progression, and which are remediable or potentially modifiable, in
order to intervene at the earliest possible stage and improve the associated adverse outcomes.
6.2.2
What factors are associated with progression of CKD: (a) cardiovascular disease; (b) acute
kidney injury; (c) obesity; (d) smoking; (e) urinary tract obstruction; (f) ethnicity; (g) chronic
use of NSAIDs?
Methodological introduction
Hypertension, diabetes mellitus, and proteinuria/albuminuria are well-established factors that
promote progression of CKD. The literature was reviewed to examine additional promoters of
renal disease progression: cardiovascular disease, acute kidney injury, obesity, smoking, urinary
tract obstruction, ethnicity, and chronic use of non-steroidal anti-inflammatory drugs
(NSAIDs). There were no studies examining acute kidney injury or urinary tract obstruction
on progression of CKD.
In a pooled analysis of the ARIC Study and Cardiovascular Health Studies (CHS), kidney
function decline (serum creatinine increase 0.4 mg/dl or a GFR decrease 15 ml/min/1.73 m2)
in people with cardiovascular disease (N=1787, mean age 60 years) was compared with people
without cardiovascular disease (N=12,039, mean age 57 years, 9.3 years follow-up).147
78
A Swedish case series investigated the effect of BMI on progression to RRT in people with stage 4
and 5 CKD (N=920, mean follow-up 2 years).170
The effect of smoking on renal functional decline was examined in two diabetic cohort studies
and two case-control studies. A diabetic cohort of smokers (N=44, mean age 47 years, 86% had
baseline proteinuria >0.15 g/day) were followed for 5.1 years (median) and changes in
proteinuria and GFR (20% decline) were compared with non-smokers (N=141, mean age
54 years, 72% had baseline proteinuria >0.15 g/day).171 In a Danish cohort of people with
type 1 diabetes and persistent albuminuria >300 mg/24 h, changes in GFR during a median
follow-up of 7 years were compared between smokers (N=176), non-smokers (N=94) and exsmokers (N=31).172 In a case-control study, men with autosomal dominant polycystic kidney
disease (ADPKD) or immunoglobulin-A glomerulonephritis (IgA-GN) who had progressed to
ESRD were matched with controls with ADPKD or IgA-GN who had not progressed to ESRD.
Progression to ESRD was compared between males who smoked for 05 pack-years (N=73),
515 pack years (N=28), or >15 pack years (N=43).173 In a Spanish case control study, cases
(people who had progressed to ESRD, N=520) were age-, sex- and hospital-matched with
controls (hospital patients who had not progressed to ESRD, N=982) and the effects of smoking
compared with non-smoking on progression to ESRD were analysed.174
An English cross-sectional study of renal units examined rates of acceptance to RRT in Caucasians
compared with Asians or blacks (N=5901).23 A London, UK case series investigated doubling of
serum creatinine and the rate of serum creatinine increase in Caucasian (N=24), Indo-Asian
(N=10), and African-Caribbean (N=11) people with type 2 diabetes and nephropathy.175 A case
series of US Medicare beneficiaries over 65 years old examined progression to ESRD in black
(N=94,511) compared with white people (N=1,163,868) in the presence of diabetes, hypertension
or neither comorbid condition. It was difficult to determine whether these participants had CKD
at baseline.176
Four studies assessed the effect of chronic NSAID use on progression of renal disease. One small,
open-label RCT compared changes in creatinine clearance and adverse events with chronic use of
ibuprofen, piroxicam, or sulindac in adults aged over 65 years with (CrCl <70 ml/min, N=15) or
without renal insufficiency (CrCl >70 ml/min, N=14) 177. In two Spanish case control studies,
cases (people who had progressed to ESRD, N=520) were age-, sex- and hospital-matched with
controls (hospital patients who had not progressed to ESRD, N=982) and the effects of chronic
use of salicylates, pyrazolones and non-aspirin NSAIDs on progression to ESRD were
analysed.174,178 In a Swedish case-control study, cases (patients with chronic renal failure,
N=926) were age and sex matched to controls (N=998) and the risk of chronic renal failure
(serum creatinine >3.4 mg/dl in men or >2.8 mg/dl in women) in regular or sporadic users of
aspirin was compared with non-users.179
Table 6.3 (page 81) summarises risk factors for progression of CKD.
6.2.3
79
6.2.4
s
Evidence statements
Effect of cardiovascular disease on progression of CKD
People with baseline cardiovascular disease had a significantly increased risk of a decline in
renal function compared with people without CVD at baseline.147 (Level 3)
80
In two case-control studies, users of salicylates had a significantly increased risk of ESRD
compared with nonusers. Users of pyrazolones had NS risk of ESRD compared with nonusers.
Users of non-aspirin NSAIDs had NS risk of ESRD compared with nonusers.174,178 (Level 2+)
In a case-control study, an average intake >500 g/year of aspirin significantly increased the risk of
chronic renal failure (adjusted OR 3.3, 95% CI 1.48.0). Sub-analysis showed regular use of aspirin
compared with non-use of aspirin was significantly associated with increased risk of chronic renal
failure in people with diabetic nephropathy, glomerulonephritis, nephrosclerosis, or hereditary
renal disease.179 (Level 2+)
Table 6.3 Summary of risk factors for progression of CKD with associated odds ratios (OR) or relative risks
(RR). 95% confidence levels in parentheses
Reference
Study
Risk factor
Population
Outcome
Effect size
147
Case series
Cardiovascular
disease (CVD)
No baseline CVD
12039
Serum creatinine
increase of 0.4 mg/dl
Reference group
Baseline CVD
1787
Serum creatinine
increase of 0.4 mg/dl
OR 1.70
(1.362.13),
p<0.001
No baseline CVD
12039
GFR decrease of
15 ml/min/1.73 m2
Reference group
Baseline CVD
1787
GFR decrease of
15 ml/min/1.73 m2
OR 1.28
(1.131.46),
p<0.001
CKD + BMI
20.125 kg/m2
377
Reference group
CKD + BMI
20 kg/m2
77
RR 1.26
(0.951.67)
CKD + BMI
25.130 kg/m2
314
RR 0.79
(0.670.94)
CKD + BMI
>30 kg/m2
26
RR 0.86
(0.681.07)
Non-smokers +
diabetic
nephropathy
141
Reference group
Smokers + diabetic 44
nephropathy
OR 2.52
(1.065.99),
p<0.01
Non-smokers +
diabetic
nephropathy
170
171
Case series
Cohort
Obesity
Smoking
141
Smokers + diabetic 44
nephropathy
81
Table 6.3 Summary of risk factors for progression of CKD with associated odds ratios (OR) or relative risks
(RR). 95% confidence levels in parentheses continued
Reference
Study
Risk factor
Population
Outcome
Effect size
172
Cohort
Smoking
Non-smokers +
type 1 diabetic
nephropathy
94
GFR Decline
mean decline
Ex-smokers +
type 1 diabetic
nephropathy
31
GFR Decline
mean decline
3.4 ml/min/year
Smokers + type 1
diabetic
nephropathy
176
GFR Decline
mean decline
4.0 ml/min/year
NS differences
between groups
Men smoking
05 pack-years
Cases=26
ESRD
Controls=47
Reference group
Men smoking
515 pack-years
Cases=17
ESRD
Controls=11
OR 3.5 (1.39.6),
p=0.017
Men smoking
>15 pack-years
Cases=29
ESRD
Controls=14
OR 5.8 (2.017),
p=0.001
Men smoking
05 pack-years
and no ACEI
No ACEI
ESRD
use:
cases=54
controls=42
Reference group
173
174
23
Case control
Smoking
(ADPKD and
IgA-GN with
ESRD matched
to non-ESRD
controls)
4.4 ml/min/year
Men smoking
>5 pack-years and
no ACEI
ESRD
Men smoking
05 pack-years
and received ACEI
ACEI use:
ESRD
cases=18
controls = 30
Men smoking
>5 pack-years and
received ACEI
ESRD
1.4 (0.37.1),
p=0.65
ESRD
Reference group
OR 10.1 (2.345),
p=0.002
Reference group
Case control
Smoking
(patients with
ESRD matched
to non-ESRD
controls)
Non-smokers
Not stated
Smokers
Cases=320 ESRD
Controls=577
OR 1.54
(1.142.07)
Cross-sectional Ethnicity
Caucasian men
3063
Acceptance to RRT
Reference group
Asian men
262
Acceptance to RRT
RR 3.1 (2.73.5)
Black men
161
Acceptance to RRT
RR 3.0 (2.63.5)
Caucasian women
1871
Acceptance to RRT
Reference group
Asian women
178
Acceptance to RRT
RR 3.9 (3.34.5)
Black women
111
Acceptance to RRT
RR 3.4 (2.84.1)
continued
82
Table 6.3 Summary of risk factors for progression of CKD with associated odds ratios (OR) or relative risks
(RR). 95% confidence levels in parentheses continued
Reference
Study
Risk factor
Population
175
Case series
Ethnicity
176
Case series
Ethnicity
Outcome
Effect size
Indo-Asian people 10
with type 2 diabetes
and nephropathy
Doubling of serum
creatinine
100%
Caucasians with
type 2 diabetes
and nephropathy
24
Doubling of serum
creatinine
50%, p=0.025
African-Caribbean
people with type 2
diabetes and
nephropathy
11
Doubling of serum
creatinine
45%, p=0.025
Indo-Asian people 10
with type 2 diabetes
and nephropathy
Rate of serum
creatinine increase
5.36 mol/l/month
Caucasians with
24
type 2 diabetes and
nephropathy
Rate of serum
creatinine increase
2.22 mol/l/month,
p=0.031
African-Caribbean
people with type 2
diabetes and
nephropathy
11
Rate of serum
creatinine increase
3.14 mol/l/month,
p=0.031
Not stated
ESRD
Reference group
Not stated
ESRD
HR 2.12
(1.902.36)
Not stated
ESRD
Reference group
Not stated
ESRD
HR 2.05
(1.872.25)
White men, no
hypertension, no
diabetes
Not stated
ESRD
Reference group
Black men, no
hypertension, no
diabetes
Not stated
ESRD
HR 3.27
(2.554.19)
continued
83
Table 6.3 Summary of risk factors for progression of CKD with associated odds ratios (OR) or relative risks
(RR). 95% confidence levels in parentheses continued
Reference
Study
Risk factor
Population
Outcome
Effect size
177
RCT
Chronic NSAID
use
1 month of
ibuprofen in people
with CrCl
<70 ml/min
15
Change in creatinine
clearance from
baseline
1 month of
15
piroxicam in people
with CrCl
<70 ml/min
Change in creatinine
clearance from
baseline
1 month of sulindac 15
in people with
CrCl <70 ml/min
Change in creatinine
clearance from
baseline
Non-users of
salicylates
ESRD
Reference group
178
174
179
Case control
Chronic NSAID
(patients with
use
ESRD matched
to non-ESRD
controls)
Case control
Chronic NSAID
(patients with
use
ESRD matched
to non-ESRD
controls)
Case control
(patients with
CRF matched
with non-CRF
controls)
Chronic NSAID
use
84
Not stated
OR 2.54
(1.245.20)
Non-users of
pyrazolones
Not stated
Reference group
Users of
pyrazolones
Cases=15
ESRD
Controls=13
OR 2.16
(0.875.32)
Non-users of
aspirin
Not stated
Reference group
Users of Aspirin
Cases=81
ESRD
Controls=94
OR 1.56
(1.052.30)
Non-users of
pyrazolones
Not stated
Reference group
Users of
pyrazolones
Cases=34
ESRD
Controls=51
OR 1.03
(0.601.76) NS
Not stated
Reference group
ESRD
ESRD
ESRD
ESRD
OR 0.94
(0.571.56) NS
Non-users of
aspirin
Cases=224
Controls=
363
Reference group
Sporadic users of
aspirin
Cases=459
Controls=
496
OR 1.5
(1.21.8)
Regular users of
aspirin
Cases=213
Controls=
141
OR 2.5
(1.93.3)
6.2.5
6.2.6
RECOMMENDATIONS
R28
Work with people who have risk factors for progression of CKD to optimise their health.
These risk factors are:
G
cardiovascular disease
G
proteinuria
G
hypertension
G
diabetes
G
smoking
G
black or Asian ethnicity
G
chronic use of non-steroidal anti-inflammatory drugs (NSAIDs)
G
urinary outflow tract obstruction.
R29
In people with CKD the chronic use of NSAIDs may be associated with progression and acute
use is associated with a reversible fall in glomerular filtration rate (GFR). Exercise caution
when treating people with CKD with NSAIDs over prolonged periods of time. Monitor the
effects on GFR, particularly in people with a low baseline GFR and/or in the presence of other
risks for progression.
85
7 Referral criteria
7.1
7.1.1
Clinical introduction
What do nephrologists do for patients with CKD? The answer to this predominantly lies in
3 main areas: diagnosis and treatment of treatable kidney disease, identification and control of
risk factors for progression of CKD and planning for renal replacement therapy in patients
progressing to end stage renal disease.
The area that has deservedly received the most attention is planning for renal replacement
therapy. There is abundant literature detailing the negative effect of late referral of patients with
advanced CKD. Late referral leads to increased morbidity and mortality, increased length of
hospital stay, and increased costs.57,180182 Several factors contribute to the adverse outcomes
associated with late referral, including untreated anaemia, bone disease, hypertension and
acidosis. The dominant factor though is insufficient time to prepare the patient for dialysis,
particularly the establishment of permanent vascular access for haemodialysis.
A CKD management programme encompasses blood pressure control and reduction of
proteinuria, treatment of hyperlipidaemia, smoking cessation and dietary advice, treatment of
anaemia, treatment of acidosis and metabolic bone disease, and just as importantly, the
provision of timely and understandable information and education.
The converse question though is how much of what nephrologists do could be done just as
safely and effectively in primary care, and how much of an overlap is there between nephrology,
diabetes, cardiology and the care of older people?
I
7.1.2
Methodology
Due to the difficulty in searching this question, the results of a broad literature search were
reviewed for systematic reviews on criteria for referral to specialist care in a CKD population.
Seven papers were identified and all were excluded as they were narrative reviews or guidelines.
7.1.3
7.1.4
Evidence statements
There are no evidence statements.
7.1.5
The GDG consensus was that the principles guiding referral should be: early identification of
people likely to require renal replacement therapy, the need for additional input to the
management of CKD, e.g. for uncontrolled hypertension, the need for specialist advice about
rare or genetic causes of CKD and the need to access specialist investigations such as magnetic
resonance angiography.
The GDG noted that section 5 and section 6 of the guideline had reviewed evidence relating to
level of eGFR, proteinuria and risk factors for CKD and progression of CKD. From this
evidence a consensus was reached regarding appropriate referral criteria in these areas.
The GDG agreed that all people with a rapidly declining GFR and those with stage 4 and 5 CKD
(with or without diabetes) should be referred, as well as those with heavy proteinuria unless this
was already known to be due to diabetes and was being appropriately treated.
The GDG agreed that specialist care can be provided by GPs, specialist nurses, renal nurses,
geriatricians, diabetologists, cardiologists and nephrologists and that referral did not
necessarily mean that the individual had to attend an out-patient clinic. In some situations
advice could be obtained by correspondence. Furthermore, once an individual had been seen
in a specialist clinic and a management plan agreed, it may be possible for their future care to
be carried out by the referring clinician rather than the specialist.
The GDG recommended that if people with lower urinary tract symptoms required referral,
this should initially be to urological services.
88
7.1.6
RECOMMENDATIONS
R30
People with CKD in the following groups should normally be referred for specialist assessment:
G
stage 4 and 5 CKD (with or without diabetes)
G
heavy proteinuria (ACR 70 mg/mmol, approximately equivalent to PCR 100 mg/mmol,
or urinary protein excretion 1g/24 hours) unless known to be due to diabetes and already
appropriately treated
G
proteinuria (ACR 30 mg/mmol, approximately equivalent to PCR 50 mg/mmol, or
urinary protein excretion 0.5 g/24 hours) together with haematuria
G
rapidly declining eGFR (>5 ml/min/1.73 m2 in one year, or >10 ml/min/1.73 m2 within
5 years)
G
hypertension that remains poorly controlled despite the use of at least 4 antihypertensive
drugs at therapeutic doses (see NICE clinical guideline 34, Hypertension: management of
hypertension in adults in primary care)
G
people with, or suspected of having rare or genetic causes of CKD
G
suspected renal artery stenosis.
R31
Consider discussing management issues with a specialist by letter, email or telephone in cases
where it may not be necessary for the person with CKD to be seen by the specialist.
R32
Once a referral has been made and a plan jointly agreed, it may be possible for routine followup to take place at the patients GP surgery rather than in a specialist clinic. If this is the case,
criteria for future referral or re-referral should be specified.
R33
Take into account the individuals wishes and comorbidities when considering referral.
R34
People with CKD and renal outflow obstruction should be referred to urological services,
unless urgent medical intervention is required, e.g. for treatment of hyperkalaemia, severe
uraemia, acidosis or fluid overload.
8 Self management
8.1
Modification of lifestyle
8.1.1
Clinical introduction
The increased prevalence of CKD has been linked to lifestyle-related factors such as hypertension
and diabetic nephropathy (see NICE Clinical Guideline 34 Management of hypertension in
adults in primary care; NICE Clinical Guideline 66 Management of Type 2 diabetes; NICE
Clinical Guideline 15 Diagnosis and management of Type 1 diabetes in children, young people
and adults; and NICE Clinical Guideline 43 Obesity: the prevention, identification, assessment
and management of overweight and obesity in adults and children).28,29,183,184 Smoking has
been associated with more severe proteinuria and progression of renal failure. In rat models of
CKD, exercise training has been shown to be renoprotective.185 The association between obesity,
smoking, physical activity and CKD therefore may be important. Equally, there may be
insufficient adjustment of potential confounders. Obesity leads to CKD through diabetes and
hypertension but is it an independent risk factor for CKD? Similarly, although it is suggested that
smoking and physical inactivity contribute to progression of CKD, is this a direct or indirect
effect, and is there a relationship to gender?186
I
8.1.2
In adults with CKD, do improving lifestyle habits slow the progression of CKD?
Methodology
Modification of lifestyle habits (smoking cessation, exercise, moderate alcohol consumption,
and weight loss in obese people) was reviewed to determine if these changes would slow the
progression of CKD. There were very few lifestyle intervention studies. There were no smoking
cessation studies in a CKD population. All of these studies were limited by small sample sizes.
Observational studies that assessed the association of smoking, obesity, alcohol consumption,
or exercise with progression of CKD were therefore included.
One RCT examined changes in GFR, muscle strength, and total body potassium over 3 months
in people aged over 50 years old with CKD on a low protein diet randomised to resistance
training (N=14) or sham training (N=12).187 Another RCT examined nondiabetic people with
CKD (median GFR 25 ml/min/1.73 m2) randomised to exercise training (N=15, 18 months
follow-up, bicycle ergometer, running, swimming, and walking) or a control group (N=15,
20 months follow-up, mostly sedentary lifestyle).188
A non-randomised controlled trial compared water-based aerobic activity (N=17) to control
(sedentary lifestyle, N=9, 3-month follow-up) for changes in GFR, cystatin C, and proteinuria
in people with CKD.189 This study was excluded because of small sample size and
methodological limitations.
One RCT190 and two before-and-after observational studies191,192 investigated the effect of
weight loss on renal disease progression in obese, mostly diabetic populations. The Morales et al.
RCT compared a low-calorie diet (N=20, 5-months follow-up, reduction of 500 kcal, consisting
89
of 2530% fat and 5565% carbohydrate, and protein content adjusted to 1.01.2 g/kg/day) with
a usual diet (N=10) in people with diabetic or nondiabetic nephropathy.190 The before and after
study of Saiki et al. investigated changes in BMI, creatinine clearance, and proteinuria before and
after one month of a low calorie formula diet (740 or 970 kcal/day or 1119 kcal/kg) in 22 obese,
hospitalised adults with diabetic nephropathy.191 The before and after study of Solerte et al.
compared changes in BMI, proteinuria, and renal function decline before and after 12 months of
a low calorie diet (1410 kcal/day consisting of 170 g carbohydrate, 58 g protein, 49 g fat) in
24 obese people with diabetic nephropathy.192
The effect of alcohol consumption on the risk of ESRD was examined in a case control study in
which alcohol consumption was compared between cases (people with new ESRD, N=716) and
age-match controls (general population, N=361).193 This study was rejected as several aspects
of a robust case-control study were ignored (exclusion criteria, comparison between
participants and non-participants, differentiation between cases and controls).
The effect of smoking on renal functional decline was examined in two diabetic cohort studies
and two case-control studies. A German diabetic cohort of smokers (N=44, mean age 47 years,
86% had baseline proteinuria >0.15 g/day) were followed for 5.1 years (median) and changes
in proteinuria and GFR (20% decline) were compared with non-smokers (N=141, mean age
54 years, 72% had baseline proteinuria >0.15 g/day).171 In a Danish cohort of people with type 1
diabetes and persistent albuminuria >300 mg/24 h (N=301), changes in GFR during a median
follow-up of 7 years were compared between smokers (N=176), non-smokers (N=94) and exsmokers (N=31).172 In a case-control study, men with ADPKD or IgA-GN who had progressed
to ESRD were matched with controls with ADPKD or IgA-GN who had not progressed to
ESRD. Progression to ESRD was compared between males who smoked for 05 pack-years
(N=73), for 515 pack years (N=28), and for >15 pack years (N=43).173 In a Spanish case
control study, cases (people who had progressed to ESRD, N=520) were age, sex, hospital
matched with controls (hospital patients who had not progressed to ESRD, N=982) and the
effects of smoking compared with non-smoking on progression to ESRD were analysed.174
The effect of lifestyle changes on the progression of CKD is summarised in Table 8.1 at the end
of the evidence statements.
8.1.3
8.1.4
s
Evidence statements
Exercise training: change in GFR
Median GFR decreased in both control and exercise groups but there were NS differences
between groups.188 (Level 1 +)
GFR increased in people with resistance training + low protein diet, whereas GFR decreased in
the sham training + low protein diet group (p=0.048 between groups).187 (Level 1 +)
90
8 Self management
Smoking cessation
There were no studies that examined the impact of smoking cessation on renal function in
people with CKD.
compared to non-smokers (OR 2.52, 95% CI 1.065.99, p<0.01). This relationship persisted
after adjustment for diabetes type or control, retinopathy, age, BMI, ACEI use, BP, proteinuria
(F-ratio=65.9, p <0.0001).171 (Level 2+)
In a diabetic cohort with nephropathy, GFR declined in non-smokers, ex-smokers, and smokers,
with NS differences between groups.172 (Level 2+)
Reference
Population
188
Duration
(months)
Intervention
Comparison
Outcome
Size effect
Nondiabetic people
18
(median GFR
25 ml/min/1.73m2,
range
1043 ml/min/1.73m2)
Exercise training
N=15
Control (sedentary
lifestyle)
N=15
Change in
GFR
(ml/min/month)
Exercise:
0.27
Control 0.28
NS between
groups
187
CKD (creatinine
133442 mol/l or
1.55.0 mg/dl)
Resistance
training + low
protein diet
N=14
Sham training +
low protein diet
N=12
Change in
Resistance
GFR
training: +
(ml/min/1.73m2) 1.18 ml/min/
1.73m2
Sham training:
1.62 ml/min/
1.73m2
p=0.048
between groups.
187
CKD (creatinine
133442 mol/l or
1.55.0 mg/dl)
Resistance
training + low
protein diet
N=12
190
Usual diet
N=10
Changes in
creatinine
clearance
(ml/min/
1.73 m2)
92
8 Self management
Reference
Population
191
Duration
(months)
Intervention
Comparison
Outcome
Size effect
Changes in
creatinine
clearance
(ml/s/1.73 m2)
0.68 0.77, NS
192
Obese diabetic
people with
nephropathy (urinary
protein excretion
>500 mg/day) and
diabetic retinopathy
12
Changes in
creatinine
clearance
(ml/s/1.73 m2)
80 90, p<0.01
190
Usual diet
N=10
Changes in
serum
creatinine
(mg/dl)
191
Changes in
serum
creatinine
(mol/l)
172.4 130.8,
p<0.0001
192
Obese diabetic
people with
nephropathy (urinary
protein excretion
>500 mg/day) and
diabetic retinopathy
12
Changes in
serum
creatinine
(mol/l)
145.2 101.2,
p<0.001
190
Obese (BMI
>27 kg/m2) people
with diabetic or
nondiabetic
nephropathy
Usual diet
N=10
Changes in
protein
excretion
(g/24 h)
191
Changes in
protein
excretion
(g/24 h)
3.27 1.50,
p<0.0001
192
Obese diabetic
people with
nephropathy (urinary
protein excretion
>500 mg/day) and
diabetic retinopathy.
Changes in
protein
excretion (%)
51%, p <0.01
12
continued
93
Reference
Population
190
Duration
(months)
Intervention
Comparison
Outcome
Size effect
Usual diet
N=10
Changes in
BMI (kg/m2)
191
Changes in
BMI (kg/m2)
30.4 28.2,
p<0.0001
192
Obese diabetic
people with
nephropathy (urinary
protein excretion
>500 mg/day) and
diabetic retinopathy.
12
Changes in
BMI (kg/m2)
33.5 26.2,
p<0.001
171
Diabetic patients
60
Smokers N=44
Non-smokers =141
Change in
GFR (ml/min)
Non-smokers:
107 106, NS
Smokers:
95 83,
p<0.001
172
Change in
GFR
(ml/min/year)
Non-smokers:
4.4
Ex-smokers:
3.4
Smokers: 4.0
NS between
groups
171
Diabetic patients
Smokers N= 44
Non-smokers=141
Change in
proteinuria
(g/24 h)
Non-smokers:
0.47 0.54
Smokers:
0.36 0.44
NS between
groups.
173
515 pack-years
N cases = 17
N controls = 11
>15 pack years
N cases=29
N controls = 14
05 pack-years
N cases = 26
N controls = 47
Progression to
ESRD
515 pack
years:
unadjusted OR
3.5 (95% CI
1.39.6),
p=0.017.
>15 pack years:
unadjusted OR
5.8 (95% CI
2.017),
p=0.001
60
continued
94
8 Self management
Reference
Population
174
8.1.5
Duration
(months)
Intervention
Comparison
Outcome
Size effect
N/A
Smokers
N=320 cases
N=557 controls
Non-smokers
N not stated
Progression to
ESRD OR 1.54
(95% CI
1.142.07)
8.1.6
RECOMMENDATIONS
R35
Encourage people with CKD to take exercise, achieve a healthy weight and stop smoking.
8.2
8.2.1
Clinical Introduction
Diet is considered one of the cornerstones in the treatment of CKD. Kidney function is essential
for eliminating waste material from digested food and the body. As kidney function worsens, it
may be necessary to alter a persons diet to reduce the problems resulting from the accumulation
of waste products.194 Dietary habits may be influenced by patient preference, lifestyle and cultural
factors but dietary recommendations depend on the stage of disease, biochemistry, normal
dietary intake, comorbidities and nutritional status.195 Dietary advice may include information
about energy, protein, sodium, phosphate, potassium and fluid.195 The overall aim is to prevent
malnutrition, hyperkalaemia, hyperphosphataemia, and obesity and to aid the treatment of
hypertension and (as CKD advances) alleviate uraemic symptoms. All of this must occur in the
context of any other dietary restriction a person might be following, such as a diabetic diet, to
ensure a balanced healthy diet to meet individual nutritional requirements.195
95
A real concern with respect to dietary protein restriction in people with CKD is the spontaneous
reduction in dietary protein intake with declining GFR. Spontaneous dietary protein intakes
were observed to fall from 1.1 g/kg/day for patients with creatinine clearances >50 ml/min
to 0.85 g/kg/day at 2550 ml/min, 0.70 g/kg/day at 1025 ml/min and 0.54 g/kg/day at
<10 ml/min.196 Malnutrition is both a cause and consequence of ill health; it is defined as a state
in which deficiency of nutrients such as energy, vitamins and minerals causes measurable
adverse effects on body composition, function or clinical outcome.197 It is very common in
people with CKD197 and can increase a persons vulnerability to disease and infections.198 In
people with CKD, one of the causes of malnutrition is loss of appetite secondary to uraemia.195
Too few calories lead to the breakdown of muscle to provide energy; this is a sign of
malnutrition. As kidney failure progresses, people tend to eat less, and poor nutrition can
become a major problem.195
The use of protein restricted diets for people with CKD has remained a controversial issue.199
In the 1960s people were often following the Giovanetti Diet, containing 20 g high biological
value protein to cover the essential amino acid requirements, but as dialysis became available its
use has declined.200 In the 1980s there was a renewed interest in low protein, high energy diets
as partially nephrectomised rats showed that protein restriction delayed the progression of renal
disease. This led in 1985 to the National Institute of Health (NIH) in the USA commissioning
a large multi-centre study the Modification of Diet in Renal Disease (MDRD) study199 to
investigate the effect of protein restriction on the progression of kidney disease. Although the
results of this trial did not support severely protein restricted diets, the findings focussed on
improvement in blood pressure control and the prevention of complications due to uraemia
and malnutrition and dietary phosphorus restriction to prevent renal bone disease.201
Hyperphosphataemia becomes a significant problem in CKD stages 4 and 5.202 Hyperphosphataemia has also been implicated as a risk factor for progression of CKD.203,204
Dysregulation of calcium and phosphate can eventually result in renal bone disease if they are not
controlled.202 Dietary restrictions alone are rarely enough to control phosphate in severe renal
failure and phosphate binders, taken with food to prevent intestinal absorption of phosphate, are
often prescribed (although it should be noted that certain phosphate binders are only licensed for
use in patients on dialysis).205,206
Hyperkalaemia is also a problem in people with advanced renal failure.207 Dietary potassium
should not be restricted routinely, only in those with raised serum levels, as potassium
containing foods are required for a healthy balanced diet and restrictions need to be carefully
monitored.195
I
8.2.2
What dietary interventions are associated with improved renal outcomes in adults with CKD?
Methodology
The utility of low protein, low phosphate, low sodium, or low potassium diets in delaying
progression of renal disease was reviewed in diabetic and nondiabetic populations with CKD.
Non-randomised trials were excluded, as were any studies in which compliance with the
randomised diet was poor. Meta-analyses that combined trials in diabetic and nondiabetic renal
disease populations were excluded. The outcomes of interest were decline in GFR or creatinine
clearance, increasing proteinuria, progression to end stage renal disease (dialysis or renal
96
8 Self management
8.2.3
8.2.4
s
Evidence statements
Renoprotective effects of low protein diets (LPDs) compared with usual protein
diets (UPDs) in nondiabetic nephropathy
Protein intake was significantly lower in the LPD group compared with UPD, but compliance
was a problem as few achieved the target protein level in the LPD group.208,209
showed NS differences in creatinine clearance between LPD and UPD.212 One RCT showed NS
differences between LPD and UPD for serum creatinine increases,213 whereas another RCT214
showed a beneficial effect of a LPD on serum creatinine changes. (Level 1+)
Renoprotective effects of low protein diets compared with usual protein diets in
diabetic nephropathy
The intended protein intake in the LPD group ranged from 0.30.8 g/kg/day, however
compliance was low as the actual protein intake ranged from 0.61.1 g/kg/day.210
Change in GFR
In people with type 1 diabetes and nephropathy, there was NS improvement in GFR in those
randomised to a LPD compared with UPD (7 RCTs, N=222). There was significant heterogeneity
(I2=62%, p=0.01). In people with type 2 diabetes and nephropathy, there was a NS improvement
in GFR in the LPD group compared with the UPD (1 RCT, N=160). Another RCT in people with
type 2 diabetes and nephropathy (N=37) showed a similar decline in GFR in the LPD compared
with the UPD group. In one RCT in which people with type 1 and type 2 diabetes and
nephropathy were combined (N=80), there were NS differences in GFR decline between those
randomised to LPD compared with a UPD.210 (Level 1+)
Quality of life
No study assessed this outcome.
Nutritional status
Nine studies assessed nutritional status, but only 1 study found evidence of malnutrition as
serum pre-albumin and albumin significantly decreased in the LPD group compared with the
UPD group.210 Four studies showed NS differences between LPD or UPD groups for serum
albumin.215218 (Level 1+)
98
8 Self management
(N=41) and UPD (N=41) for changes in mid arm circumference in people with type 1 diabetes
and nephropathy.216 (Level 1+)
Table 8.2 Effect of a low protein diet (LPD) compared with a usual protein diet (UPD) on renal disease
progression in adults with diabetic or nondiabetic nephropathy (95% confidence intervals)
Reference
Population
Outcome
208
ESRD or death
209
ESRD or death
209
ESRD or death
209
ESRD or death
208
GFR change
208
Changes in creatinine
clearance
NS
208
Changes in serum
creatinine
1 RCT=NS
1 RCT=benefit
210
ESRD or death
210
GFR change
210
GFR change
210
8.2.5
It was noted that dietary protein intake often declines as people get older and that this is likely
to occur in people with CKD.
It was noted that apart from the risks of malnutrition, low protein diets are usually unpalatable
and are time consuming to adhere to as all portions must be weighed. These aspects are likely
to affect the quality of life of people with CKD and therefore any recommendations about
dietary restriction must have a sound evidence base.
The GDG also noted that adequate iron in the diet is important in CKD and restricting protein
intake may adversely influence iron intake.
The GDG agreed that the studies combined in the meta-analysis by Pedrini et al. were too
heterogeneous in terms of the severity of the underlying CKD for the analysis and conclusions
to be appropriate. It was also noted that some of the studies were carried out at a time when the
pharmacological management, particularly the use of ACE inhibitors, was likely to be different.
The individual studies were examined and the GDG agreed that there was limited evidence that
there may be a benefit of protein restriction in patients with stage 4 and 5 CKD, but the
evidence did not point to an optimal protein intake.
100
8.2.6
RECOMMENDATIONS
R36
Where the clinician in discussion with the patient has decided that dietary intervention to
influence progression of CKD is indicated, an appropriately trained professional should
discuss the risks and benefits of dietary protein restriction, with particular reference to
slowing down the progression of disease versus protein-calorie malnutrition.
R37
Where dietary intervention is agreed this should occur within the context of education,
detailed dietary assessment and supervision to ensure malnutrition is prevented.
R38
Offer dietary advice to people with progressive CKD concerning potassium, phosphate,
protein, calorie and salt intake when indicated.
9.1.1
Clinical introduction
There is strong evidence that lowering blood pressure reduces cardiovascular risk and progression
of CKD. The optimal treatment target remains poorly defined and considerable confusion has
occurred because there is a lack of conformity between recommended treatment targets in
different disease guidelines and in the Quality and Outcomes Framework. The objective of this
section was both to consider the evidence and to rationalise treatment targets with those
recommended by the NICE guidelines for management of type 2 diabetes and hypertension.
General aspects of blood pressure management will not be covered in this guideline but for advice
relating to measuring blood pressure and lifestyle interventions to reduce blood pressure please
see NICE clinical guideline 34 (Hypertension: management of hypertension in adults in primary
care). Although the hypertension guideline did not recommend home monitoring recent data
shows that self-measurement leads to less medication use than clinic blood pressure
measurement without leading to significant differences in outpatient values of blood pressure.219
The UK CKD guidelines15 recommended that the threshold for initiation and subsequent adjustment of antihypertensive therapy should be 140/90 mmHg for patients without proteinuria, and
130/80 mmHg for those with a PCR >100 mg/mmol. Antihypertensive therapy should be adjusted
to achieve blood pressure <130/80, or <125/75 mmHg for those with a PCR >100 mg/mmol. The
Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines35 recommend achieving blood
pressure <130/80 mmHg and the SIGN guidelines32 recommend a target maximum systolic blood
pressure of 130 mmHg in those with 1 g/day of proteinuria. CARI guidelines are more
proscriptive, recommending a target blood pressure of <125/75 mmHg in those with proteinuria
>1 g/day but acknowledging that the precise goal below 130/80 mmHg is not clear. The British
Hypertension Society guidelines define optimal blood pressure control in people with kidney
disease as <130/80 mmHg and suggest reducing blood pressure to <125/75 mmHg in those with
proteinuria 1 g/24 h.1,220
9.1.2
In adults with proteinuric/nonproteinuric CKD, what are the optimal blood pressure ranges
for slowing kidney disease progression, and for reducing cardiovascular disease risk and
mortality?
Methodology
One meta-analysis, three randomised controlled trials, four case series studies, and five posthoc analyses of RCTs, examined the effects of intense versus usual blood pressure control on
renal and cardiovascular outcomes in people with diabetic or nondiabetic kidney disease. All
post-hoc analyses of RCTs were downgraded to level two evidence.1 The long-term follow-up
study of the MDRD trial221 was rejected because blood pressure measurements were not
recorded during the follow-up period and participants were not advised to maintain their
originally randomised diet and antihypertensive regimens.
101
The effects of blood pressure control on cardiovascular and renal outcomes in people with CKD
are summarised in Tables 9.2 and 9.3 at the end of the evidence statements.
9.1.3
9.1.4
s
Evidence statements
Cardiovascular outcomes
The African American Study of Kidney Disease and Hypertension (AASK) RCT (N=1094,
follow-up 4 years),222 compared the effect of intense (MAP 92 mmHg) versus usual (MAP
102107 mmHg) blood pressure control on cardiovascular outcomes in African-American
adults with proteinuric, hypertensive nondiabetic kidney disease.
A case series (N=860, follow-up 10 years) investigated the association of systolic blood
pressures <133 mmHg and mortality in a cohort of men (mean age 6810 years) with stages 3
to 5 CKD.223 Another case series (N=1549, mean follow-up 8.8 years) examined the effect of
SBP <120 mmHg on stroke in elderly people (mean age 70.210.3 years) with stages 3 and 4
CKD.224 This study lacked data on baseline proteinuria.
Two post-hoc analyses of the Irbesartan in Diabetic Nephropathy Trial (IDNT) RCT (N=1590,
median follow-up 2.9 years)225,226 suggested that systolic blood pressures <120 mmHg were
associated with poor cardiovascular outcomes and increased all-cause mortality in proteinuric
diabetic kidney disease. Diastolic blood pressure was not significantly associated with all-cause
mortality, cardiovascular mortality, or congestive heart failure.225 These results should be
interpreted with caution as the number of participants with systolic blood pressure <120 mmHg
was small (N=53).
All-cause mortality
In the AASK trial, people assigned to usual versus intense blood pressure control had NS
difference in the risk for all-cause mortality.222 (Level 1+)
People with diabetic nephropathy and overt proteinuria with an achieved SBP 120 mmHg
(N=53) had a significantly greater risk of all-cause mortality compared to people with an
achieved SBP >120 mmHg (N=1537).225,226 (Level 2+)
In US veterans with stage 35 CKD, men with SBP 134154 mmHg (N=238) had a significantly
decreased risk for all-cause mortality compared with men who had SBP <133 mmHg
(N=217).223 Mortality was highest in men with DBP <64 mmHg and lowest in men with DBP
>86 mmHg. (Level 3)
There was a significant reduction in the risk for all-cause mortality for men with DBP
>86 mmHg (N=200) compared with DBP <65 mmHg (N=233).223 (Level 2 + and 3)
Cardiovascular mortality
In the AASK trial, people assigned to usual versus intense blood pressure control had NS
difference in the risk for cardiovascular mortality.222 (Level 1+)
102
In people with diabetic nephropathy and overt proteinuria, the risk of cardiovascular mortality
decreased as achieved SBP decreased from >170 mmHg to 120130 mmHg. There was a
significantly higher risk of cardiovascular mortality for people with an achieved SBP <120 mmHg
compared with SBP >120 mmHg.225 (Level 2+)
Myocardial infarction
People with diabetic nephropathy and overt proteinuria and an achieved SBP 120 mmHg
had NS difference in risk of MI compared to people with an achieved SBP >120 mmHg.225
(Level 2 +)
The risk for MI was significantly higher in people with DBP <70 mmHg (no numerical data
provided) compared to the reference DBP 7080 mmHg. (Level 2 +)
The risk for MI was significantly lower in people with DBP >85 mmHg (no numerical data
provided) compared to the reference DBP 7080 mmHg.225 (Level 2 +)
Stroke
People with diabetic nephropathy and overt proteinuria and an achieved SBP 120 mmHg
had NS difference in risk of stroke compared to people with an achieved SBP >120 mmHg.225
(Level 2 +)
In contrast, a case series of people with stage 3 to 4 CKD (no proteinuria data provided) showed
a SBP <120 mmHg (N=209) significantly increased the risk for stroke compared with a SBP
120129 mmHg (N=173).224 (Level 3)
Renal outcomes
One meta-analysis of eleven randomised controlled trials (N=1860, mean follow-up 2.2 years)
evaluated the effect of increasing systolic blood pressures and proteinuria on the progression of
kidney disease in predominantly nondiabetic proteinuric CKD populations.227
The effects of intense versus usual blood pressure control on renal outcomes in adults with
proteinuric, nondiabetic kidney disease were analysed in three randomised controlled trials: the
MDRD RCT (N=840, mean follow-up 2.2 years),201 the REIN-2 RCT (N=338, median followup 1.6 years)228 and the AASK RCT (N=1094, follow-up 4 years).222 Table 9.1 details the blood
pressure goals of each RCT.
103
MDRD
REIN-2
AASK
MAP 92 mmHg
Two post-hoc analyses of RCTs conducted in proteinuric diabetic populations investigated the
impact of blood pressure control on renal outcomes: the IDNT (N=1590, mean follow-up
2.9 years)226 and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist
Losartan study (RENAAL) (N=1513, median follow-up 3.4 years).229
In a type 1 diabetic kidney disease cohort (N=301, follow-up 7 years, mean age 36 years)
participants who achieved regression (GFR decline <1 ml/min/year) or remission (decrease in
albuminuria <200 g/min sustained for at least one year) of renal disease were compared with
participants who failed to achieve regression or remission in terms of levels of blood pressure
control, albuminuria, and GFR decline.230
The Leiden 85-Plus case series (N=550, age range 8590 years, follow-up 5 years, no proteinuria
data) assessed the effect of blood pressure on the decline in creatinine clearance over time in an
elderly cohort.231
104
between people with achieved SBP 130139 mmHg (N=401) compared to people with achieved
SBP <130 mmHg (N=278).229 (Level 2 +)
There was NS difference in risk for the combined renal endpoint at achieved DBP 7089 mmHg
compared with achieved DBP <70 mmHg. People with an achieved DBP <70 mmHg (N=365)
had a significantly lower risk of reaching the combined renal endpoint compared with those
with an achieved DBP of 9099 mmHg (N=152).229 (Level 2+)
Progression to ESRD
In the AASK and REIN-2 trials, there was NS risk for ESRD between intense or usual control.
(Level 1+)
In post-hoc analysis of the RENAAL trial, there was NS difference in risk for reaching ESRD for
people with achieved SBP 130139 mmHg (N=392) compared with people with achieved SBP
<130 mmHg (N=286). Achieved SBP 140159 mmHg (N=518) was associated with a significantly
higher risk of reaching ESRD compared with achieved SBP <130 mmHg (N=286). (Level 2 +)
There was NS difference in risk for ESRD at achieved DBP 7089 mmHg compared with achieved
DBP <70 mmHg. Achieved DBP of 9099 mmHg (N=144) was associated with a significantly
higher risk of reaching ESRD compared to achieved DBP <70 mmHg (N=377).229 (Level 2 +)
Proteinuria
In the AASK trial, proteinuria was significantly decreased by 17% in the intense control group,
whereas proteinuria increased by 7% in the usual control group (p<0.001). (Level 1+)
105
In the REIN-2 trial, there was NS difference in proteinuria between those with intensive
(N=167) BP control compared to those with conventional (N=168) BP control. (Level 1+)
In post-hoc analysis of the MDRD trial,232 assignment to intense control significantly decreased
proteinuria during follow-up compared to usual control. This was seen in people with baseline
proteinuria >0.25 g/day. (Level 2+)
Remission
Remission was defined as a decrease in albuminuria <200 g/min in at least two out of three
consecutive 24-hour urine collections that was sustained for at least one year during follow-up,
with a decrease of at least 30% from pre-remission levels.
In a cohort of type 1 diabetic patients with nephropathy (N=301), more people with a lower
follow-up MAP achieved remission. Stratified by MAP: MAP 93 mmHg (58% remission), MAP
99 mmHg (33% remission), MAP 103 mmHg (25% remission), MAP 107 mmHg (20%
remission), MAP 113 mmHg (17% remission).230 (Level 3)
Table 9.2 Cardiovascular and renal outcomes according to SBP or MAP control in adults with either diabetic
or nondiabetic CKD stratified by baseline urinary protein excretion rate (95% confidence interval)
Nondiabetic CKD
Outcome
<1 g/day
proteinuria
>1 g/day
proteinuria
Diabetic CKD
<1 g/day
proteinuria
>1 g/day
proteinuria
All-cause mortality
HR 0.62 (0.450.85),
p=0.003
SBP 134154 mmHg
vs. 133 mmHg
(US vet)
RR 3.05 (1.805.17),
p<0.0001
SBP 120 mmHg vs.
SBP >120 mmHg
(IDNT*)
Cardiovascular
mortality
RR 4.06 (2.117.80),
p<0.0001
SBP 120 mmHg vs.
SBP >120 mmHg
(IDNT*)
Congestive heart
failure
RR 1.80 (1.172.86),
p=0.008
SBP 120 mmHg vs.
SBP >120 mmHg
(IDNT*)
continued
106
Table 9.2 Cardiovascular and renal outcomes according to SBP or MAP control in adults with either diabetic
or nondiabetic CKD stratified by baseline urinary protein excretion rate (95% confidence interval) continued
Nondiabetic CKD
Diabetic CKD
Outcome
<1 g/day
proteinuria
>1 g/day
proteinuria
<1 g/day
proteinuria
>1 g/day
proteinuria
Myocardial infarction
NS 120 vs.
>120 (IDNT*)
Stroke
HR 2.26 (1.164.41)
NS 120 vs.
>120 (IDNT*)
Decline in GFR or
creatinine clearance
Doubling serum
creatinine, ESRD,
or death
NS risk SBP
130139 mmHg vs.
SBP <130 mmHg
HR 1.49 (1.181.90),
p=0.001
SBP 140159 mmHg
vs. SBP <130 mmHg
(RENAAL*)
ESRD or death
NS difference in risk
SBP 130139 mmHg
vs. SBP <130 mmHg
HR 1.33 (1.021.72),
p=0.03
SBP 140159 mmHg
vs. SBP <130 mmHg
vs. (RENAAL*)
ESRD
NS risk SBP
130139 mmHg vs.
SBP <130 mmHg
HR 1.52 (1.072.15),
p=0.02
SBP 140159 mmHg
vs. SBP <130 mmHg
(RENAAL*)
Doubling serum
creatinine or ESRD
continued
107
Table 9.2 Cardiovascular and renal outcomes according to SBP or MAP control in adults with either diabetic
or nondiabetic CKD stratified by baseline urinary protein excretion rate (95% confidence interval) continued
Nondiabetic CKD
Outcome
Proteinuria
Diabetic CKD
<1 g/day
proteinuria
>1 g/day
proteinuria
<1 g/day
proteinuria
>1 g/day
proteinuria
Proteinuria intense
MAP control (AASK)
Proteinuria intense
MAP control (MDRD*)
NS difference intense
vs. usual MAP control
(REIN-2)
Proteinuria intense
MAP control (MDRD*)
*Post-hoc analysis.
Table 9.3 Cardiovascular and renal outcomes according to DBP control in adults with either diabetic or
nondiabetic CKD stratified by baseline urinary protein excretion rate
Nondiabetic CKD
Diabetic CKD
Outcome
<1 g/day
proteinuria
>1 g/day
proteinuria
<1 g/day
proteinuria
>1 g/day
proteinuria
All-cause mortality
HR 0.6 (0.40.9,
DBP not predictive
p=0.005).
(IDNT*)
DBP >86 mmHg vs.
DBP <65 mmHg (US vet)
Cardiovascular
mortality
Congestive heart
failure
Myocardial infarction
Stroke
RR 0.65 (0.480.88),
p=0.005
10 mmHg lower
achieved DBP vs.
85 mmHg DBP) (IDNT*)
Decline in GFR or
creatinine clearance
(CrCl decline
1.63 ml/min) vs.
DBP 7079 mmHg
(1.21 ml/min, p=0.01)
or DBP 80-89 mmHg
(1.26 ml/min, p=0.03).
NS difference in CrCl
decline for DBP <70 mmHg
vs. DBP 90 mmHg.
(Leiden 85-Plus;
16% diabetic, no
proteinuria data)
continued
108
Table 9.3 Cardiovascular and renal outcomes according to DBP control in adults with either diabetic or
nondiabetic CKD stratified by baseline urinary protein excretion rate continued
Nondiabetic CKD
Diabetic CKD
<1 g/day
proteinuria
>1 g/day
proteinuria
<1 g/day
proteinuria
>1 g/day
proteinuria
Doubling serum
creatinine, ESRD,
or death
NS risk DBP
7089 mmHg vs.
DBP <70 mmHg.
HR 1.72 (1.322.23),
p<0.001
DBP 9099 mmHg vs.
DBP <70 mmHg
(RENAAL*)
ESRD or death
NS risk DBP
70-89 mmHg vs.
DBP <70 mmHg.
HR 1.55 (1.162.08),
p=0.003
DBP 9099 mmHg vs.
DBP <70 mmHg
(RENAAL*)
ESRD
NS risk DBP
7089 mmHg vs.
DBP <70 mmHg.
HR 1.67 (1.152.44),
p=0.008
DBP 9099 mmHg vs.
DBP <70 mmHg
(RENAAL*)
Doubling serum
creatinine or ESRD
Outcome
*Post-hoc analysis.
9.1.5
109
The evidence suggests that the optimal blood pressure range is not influenced by age and the
studies considered have included people aged up to 80.
In people with CKD without diabetes, there is some evidence to suggest lower blood pressure
targets in those with a threshold level of proteinuria equivalent to an ACR of 70 mg/mmol, or
PCR 100 mg/mmol (approximately equivalent to urinary protein excretion of 1 g/day).
In order to be consistent with the available evidence on ACEI/ARB therapy a threshold level of
proteinuria at which ACEI/ARBs should also be recommended for blood pressure control in
people without diabetes was set at an ACR of 30mg/mmol, or PCR 50 mg/mmol (approximately
equivalent to a urinary protein excretion of 0.5 g/day).
9.1.6
RECOMMENDATIONS
R39
In people with CKD aim to keep the systolic blood pressure below 140 mmHg (target range
120139 mmHg) and the diastolic blood pressure below 90 mmHg.
R40
In people with diabetes and CKD or when the ACR is 70 mg/mmol, or PCR 100 mg/mmol
(approximately equivalent to PCR 100 mg/mmol, or urinary protein excretion 1.0 g/24 h)
aim to keep the systolic blood pressure below 130 mmHg (target range 120129 mmHg) and
the diastolic blood pressure below 80 mmHg.
The diagrams in Figure 9.1 are not included in the above recommendations but illustrate the
BP values that are associated with adverse outcomes.
130
140
150
160
70
80
110
90
100
9.2
9.2.1
Clinical introduction
In general, different classes of anti-hypertensives reduce blood pressure to a similar degree, and a
number of trials of anti-hypertensive therapy have shown that reduction of blood pressure reduces
the risk of end stage kidney disease and of cardiovascular disease regardless of the class of agent
employed.220,233236 NICE recommends that for people newly diagnosed with hypertension, those
younger than 55 years should be started on an ACE inhibitor or ARB, and those either over
55 years or of black ethnicity should be started on either a calcium-channel blocker or thiazidetype diuretic.28 Where blood pressure remains uncontrolled additional classes of antihypertensives such as alpha-blockers and beta-blockers are recommended. Hypertension is
extremely common in people with CKD and the mean number of antihypertensive agents
prescribed is associated with the stage of CKD, increasing as GFR falls.19
Existing guidelines are quite clear that certain anti-hypertensive agents have specific benefits in
patients with additional comorbidities and it is well known that ACEI/ARBs have additional
benefits over and above blood pressure control in people with diabetes. The UK CKD
guidelines15 recommend that ACEI/ARBs should be used as first line therapy only for people
with diabetic kidney disease and for those with proteinuria (urine PCR >100 mg/mmol) and
this was endorsed by the UK consensus conference. Although the evidence is less clear in nondiabetic kidney disease with lesser degrees of proteinuria the Quality and Outcomes Framework
requires the use of ACEI/ARBs in people with stage 35 CKD hypertension and proteinuria.
The CARI guidelines36 recommend that regimens including ACEI/ARBs are more effective in
slowing progression of non-diabetic CKD, and that combination of ACEIs and ARBs slow
progression more effectively than either single agent. They also conclude that ACEI/ARBs are
more effective than beta-blockers and dihydropyridine calcium channel blockers, and that betablockers may be more effective than dihydropyridine calcium channel blockers.
9.2.2
What are the most appropriate antihypertensive drugs to reduce the risk of progression of
CKD and to decrease mortality in adults with CKD?
Methodology
Six systematic reviews237242 and ten RCTs118,222,243250 compared the use of ACE inhibitors
and/or ARBs with placebo or other antihypertensive agents (alpha or beta blockers, calcium
channel blockers, thiazide diuretics). Most trials used non-ACEI or non-ARB antihypertensive
agents in both arms to achieve blood pressure control and to ascertain if ACEI or ARBs
provided renoprotective effects beyond blood pressure control.
The sample sizes in these studies ranged from N=180 to 39485 and the duration of the trials
ranged from 6 months to 6 years. The mean age of study participants was under sixty years of
age, with the exception of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart
Attack Trial (ALLHAT) study,118 in which the mean age was 67 or 70 in each treatment arm.
The studies were also quite heterogeneous in terms of the population studied diabetic
nephropathy or nondiabetic CKD.
111
Two studies243,246 were excluded as important features such as the number of people in each trial
arm, intention to treat analysis, baseline characteristics, or statistical power estimations were not
provided. The study by Marin et al.245 was excluded as it was not blinded and was underpowered
for the mortality outcome. A systematic review of ten RCTs241 comparing combination therapy
ACEI + ARB versus monotherapy (ACEI or ARB) in adults with diabetic nephropathy was excluded
because the quality of each included trial was not assessed; the primary outcome (proteinuria
change) had significant heterogeneity and there was no heterogeneity analysis for sub-group
analyses. Studies included in the meta-analysis were only 812 weeks long. There was wide
variation in the dosage of ACEI and ARB, and few studies titrated to the maximum tolerated dose.
9.2.3
ACEI
DNCSG (diabetes)
Captopril
Authors
Time horizon
(years)
Costs
Effects
UK
251
Italy
252
10
US
253
Lifetime
US
254
Lifetime
Germany
255
Netherlands
256
10
US
257
REIN (non-diabetes)
AIPRI (various)
112
Ramipril
Benazepril
Time horizon
(years)
UK
258
10
1.5
US
259
3, 10 and 25
Switzerland
260
25
Canadian
261
25
258
Lifetime
UK
262
Lifetime
3.5
US
263
3.5
3.5
NM
Switzerland
264
3.5
NM
NM
Canadian
265
NM
NM
France
266
NM
NM
ARB
IDNT (diabetes)
Irbesartan
RENAAL (diabetes)
Costs
Effects
Losartan
3.5
NM = not modelled.
9.2.4
s
Evidence statements
Renoprotective effects of ACE inhibitors or ARBs compared with placebo/no
treatment
One systematic review237 investigated the renoprotective effects of ACE inhibitors or ARBs
compared to placebo or no treatment in adults with diabetic kidney disease.
Another systematic review (49 RCT, N=6181, trial durations 112 months) assessed changes in
proteinuria in people with renal disease of various causes randomised to ARBs versus placebo,
calcium channel blockers, or ACE inhibitors. It also assessed combination therapy (ACEI +
ARB) versus ACEI or ARB monotherapy.242 In the combination therapy comparisons, few trials
titrated the ACEI and ARB dosage to the maximum tolerated doses.
The Ramipril Efficacy in Nephropathy (REIN) RCT compared an ACE inhibitor (ramipril)
with placebo in non-diabetic adults with CKD (N=352) stratified by baseline proteinuria:
stratum one covered 12.9 g/24 h248 and stratum two 3 g/24 h.247 Both trial arms received
non-ACEI antihypertensive agents to control blood pressure.
Risk of ESRD
There was a significant reduction in the risk of ESRD with ACEI (10 studies, N=6819, RR 0.60,
95% CI 0.390.93) or ARB (3 studies, N=3251, RR 0.78, 95% CI 0.670.91) compared with
placebo or no treatment.237 (Level 1++)
113
In adults with non-diabetic CKD and baseline proteinuria 12.9 g/24 h, ramipril (ACE
inhibitor) significantly reduced the risk of progression to ESRD by 56% compared to
placebo.248 For adults with baseline proteinuria 3 g/24 h, ramipril significantly reduced the
risk of ESRD or doubling of serum creatinine (18/78 ramipril versus 40/88 placebo, p=0.04).
A higher baseline urinary protein excretion rate was associated with a higher risk of reaching
the combined endpoint in the placebo group, but not in the ramipril group.247 (Level 1+)
Regression to normoalbuminuria
ACEI (16 studies, N=1910, RR 3.06, 95% CI 1.765.35) or ARB (2 studies, N=670, RR 1.42,
95% CI 1.051.93) significantly increased regression from micro- to normoalbuminuria
compared with placebo or no treatment. There was NS difference in regression to
normoalbuminuria for ACEI compared with ARB.237 (Level 1++)
Changes in proteinuria
In adults with baseline proteinuria 12.9 g/24 h, median proteinuria increased from baseline by
15% in the placebo group and decreased by 13% in the ramipril group (p=0.003).248 In adults
with baseline proteinuria rate 3 g/24 h, proteinuria decreased from baseline by 35% and 55%
at month 3 and month 36, respectively (p=0.002), while proteinuria did not change in the
placebo arm.247 (Level 1+)
ARBs significantly decreased proteinuria compared with placebo (6 RCTs, N=2994, 512 month
follow-up, ratio of means 0.66 (96% CI 0.630.69) or CCBs.242 (Level 1+)
Change in GFR
In adults with baseline proteinuria 12.9 g/24 h, there was NS difference in the mean GFR decline
per month in the ramipril versus the placebo group.248 In those with baseline proteinuria
114
3 g/24 h, the mean GFR decline was significantly slower in the ramipril group than the placebo
group (0.53 vs. 0.88 ml/min per month, p=0.03).247 (Level 1+)
Risk of ESRD
In the meta-analysis, ACEI or ARB use was associated with a significant reduction in the
occurrence of ESRD compared with other antihypertensive drugs (13 trials (N=37,089,
RR 0.87, 95% CI 0.750.99, p=0.04). When trials in diabetic and nondiabetic populations were
separated from each other, there was NS difference between ACEI or ARB compared with other
antihypertensive drugs 238. (Level 1+)
In a nondiabetic population, there was no significant difference between ramipril and
metoprolol in risk reduction for ESRD alone.222 (Level 1+)
Regression to normoalbuminuria
There was NS difference in regression to normoalbuminuria between people treated with
ramipril (ACEI) versus lercanidipine (calcium channel blocker).244 (Level 1+)
Changes in proteinuria
ACEI or ARBs showed a small reduction in albuminuria compared with other antihypertensive
treatments (44 trials, N=5266, mean difference 15.73, 95% CI 24.72 to 6.74, p=0.001).
However, there was significant interstudy heterogeneity (p<0.0001) and small study bias
115
(p=0.001).238 In participants with diabetic CKD, a small reduction in albuminuria was noted
for ACEI or ARBs compared with other antihypertensive treatments (34 trials, N=4772, mean
difference 12.68, 95% CI 21.68 to 2.74). In studies only including people without diabetes,
ACEI or ARBs were associated with a significant reduction in albuminuria compared with other
antihypertensive agents (8 trials, N=414 mean difference 32.30, 95% CI 49.18 to 15.42).238
(Level 1+)
In a hypertensive diabetic population with microalbuminuria (N=180), there was NS difference
between albuminuria in people treated with ramipril (ACEI) versus lercanidipine (calcium
channel blocker).244 (Level 1+)
ARBs significantly decreased proteinuria compared with calcium channel blockers (5 RCTs,
N=1432, 512 month follow-up, ratio of means 0.62 (95% CI 0.550.70).242 (Level 1+)
ACEI + ARB combination therapy significantly decreased proteinuria compared with ARB
monotherapy (7 RCTs, N=362, ratio of means 0.75, 95% CI 0.610.92).242 (Level 1+)
There was NS effect on proteinuria of ACEI versus ARB.242 (Level 1+)
Change in GFR
ACEI or ARBs had NS effect on GFR decline compared with other antihypertensive treatments.238
(Level 1+)
By contrast, in a black nondiabetic hypertensive population, the mean GFR decline was
significantly slower in the ramipril group (ACEI) than the metoprolol group (beta blocker)
(1.81 vs. 2.42 ml/min /1.73 m2, p=0.007).222 (Level 1+)
116
Stroke
There was NS difference in the risk for stroke between lisinopril or chlorthalidone for those
with mild or moderate/severe renal impairment.118 (Level 1+)
Heart failure
People with moderate/severe renal impairment receiving lisinopril had significantly increased
odds of heart failure compared with those receiving chlorthalidone (OR 1.29, 95% CI
1.061.58, p=0.011).118 (Level 1+)
Hyperkalaemia
There was NS difference in the risk of hyperkalaemia for ACEI versus placebo/no treatment.
There was a significant increase in the risk of hyperkalaemia with ARB compared with placebo
(2 studies, N=2287, RR 5.41, 95% CI 1.8715.65).237 (Level 1+)
117
Hyperkalaemia
There was no hyperkalaemia in people treated with ramipril (ACEI) versus lercanidipine
(calcium channel blocker).244 (Level 1+)
There was no significant difference in hyperkalaemia incidence between ramipril and
metoprolol.222 (Level 1+)
Risk of ESRD
The unadjusted relative risk of developing ESRD was in favour of the ACEI group, becoming
significantly less than 1 at a baseline proteinuria of >1.0 g/day. For people with baseline
proteinuria of <0.5 g/day, the relative risk of ESRD was 1.01 (95% CI 0.442.32), and 0.66 (95%
CI 0.281.56) for patients with baseline proteinuria of 0.51.0 g/day.239 (Level 1+)
There was significant interaction between baseline urine protein and ACEI therapy (interaction
p=0.003). The Kent et al. meta-analysis did not find any additional benefit of ACEI therapy
among patients with proteinuria <500 mg/day, even amongst those at high risk for progression
to ESRD. In people with urinary protein 500 mg/day, a substantial treatment effect was seen
across all risk groups.240 (Level 1+)
From the results of the AASK trial, the reduction in risk for developing the clinical outcomes of
ESRD or a halving of GFR was 38% (95% CI 1356%) for the ACEI vs. the calcium-channel
blocker comparison group and among participants with a PCR >0.22, the reduction in risk of
developing the clinical outcomes was 48% (95% CI 2066%, p=0.003).250 Another analysis of
these trial data found that the baseline level of proteinuria was an independent predictor of
change in GFR and the risk of developing ESRD.249 The risk of developing ESRD was found to
be similar in all treatment groups: ACEI, calcium channel blocker and beta-blocker, although
the magnitude of the change in GFR at 6 months was greater in the calcium channel blocker
treatment group than the ACEI or beta-blocker treatment groups. (Level 1+)
Proteinuria
One RCT250 found a significantly greater reduction in proteinuria in the ACEI treated group
compared with the control calcium channel blocker group both above and below a baseline
PCR of 0.22. Among those with PCR <0.22, the rate at which participants developed PCR 0.22
118
was 56% (95% CI 3769%) lower for the ACEI group than for the calcium-channel blocker
group.250 (Level 1+)
One of the meta-analyses found a significantly greater mean decrease in proteinuria in the ACEI
group than in the control group of 0.46 g/day (95% CI 0.330.59 g/day).239 (Level 1+)
Change in GFR
The analyses of the AASK trial all found the baseline proteinuria level to be a strong predictor
of GFR decline, with higher baseline proteinuria levels associated with significantly greater
declines in GFR.222,249,250 The Agodoa et al. study reported a significantly greater GFR decline
over three years in the ACEI treated group compared with the calcium channel blocker group
in patients who had a baseline PCR of 0.22. By contrast, the GFR decline was significantly
slower in the ACEI group than the calcium channel blocker group in people who had a baseline
PCR >0.22 (corresponding to proteinuria of >300 mg/day, p=0.006). (Level 1+)
A second paper found that baseline proteinuria did not influence the comparison of ACEI to
beta-blocker with respect to GFR change.222 (Level 1+)
9.2.5
s
119
ARBs
Economic evaluations based on the IDNT study have looked at the costs and effects in several
healthcare settings:
G
Data for ESRD projections have been published for Belgium and France but not for the
UK, USA or Canada. As the transition probabilities from the states progressing to ESRD
were taken from the IDNT rather than country-specific data, the model produced the
same projections for all countries. Over a 10-year time span the mean time to onset of
ESRD was 8.23 years for irbesartan, 6.82 years for amlodipine and 6.88 years for the
control. The mean cumulative incidence of ESRD over the 10-year time span was 45% for
control, 49% for amlodipine and 36% for irbesartan. Although the UK and the USA (and
Canada) were simulated using the same model and transition probabilities, it could be
expected that the results might be the same for these countries.
G
In summary, life expectancy was improved in the irbesartan group compared to
amlodipine and control groups in all the papers reviewed. However, in the UK study by
Palmer et al.258 life expectancy projections were reported only in relative terms,
comparing irbesartan to amlodipine and control. Treatment with irbesartan was projected
to extend life further than that with either amlodipine or control.
G
For cost analysis, irbesartan resulted in cost savings very early, usually within 23 years of
treatment for all settings. In the UK, cost savings due to avoided or delayed ESRD were
evident after 3 years compared to the amlodipine group and after 4 years compared to the
control group.
G
Based on the published evidences from various studies, it appears that irbesartan has a
valuable role in reducing the huge clinical and economic burden associated with ESRD in
patients with type 2 diabetes, hypertension and overt nephropathy.
Economic evaluations based on the RENAAL study have looked at the costs and effects in
several healthcare settings. Treatment with losartan was associated with a reduced number of
ESRD days by an average of 46.9 days per patient compared to the placebo and a net saving of:
G
C$6,554 in Canada265
G
US$7,058 in the USA263
G
5835 in France,266
G
CHF6511 in Switzerland.264
120
Also, the UK study projected 6622 net savings and the mean number of life years saved were
0.44 years.262
An economic evaluation based on the IDNT and IRMA-2 study has looked at the costs and
effects in the Canadian healthcare setting.267 Treatment with irbesartan (early and late
initiation of treatment) was compared to conventional care of people with hypertension and
type 2 diabetes. The early irbesartan strategy was dominant over both the late irbesartan and
conventional antihypertensive therapy strategies. Initiating irbesartan therapy during advanced
overt nephropathy was dominant over conventional antihypertensive therapy. Late irbesartan
treatment resulted in a mean of 0.16 life years gained and $14,300 cost savings compared with
conventional antihypertensive therapy. When irbesartan treatment is initiated early, there is a
mean of 0.45 life-years gained per patient and a cost saving of $54,100 compared with starting
irbesartan treatment later. The early irbesartan strategy was found to be cost-saving by year 5
compared with conventional treatment strategy and year 6 compared with the late irbesartan
treatment strategy.
These economic evaluations using different time horizons suggest ARBs versus conventional
therapy is cost saving for type 2 diabetes nephropathy patients, mainly because of the high costs
of dialysis and transplantation.
An economic evaluation based on a meta-analysis of randomised studies investigated the effects
of ACEI/ARB therapy on the incidence of ESRD in patients with diabetic nephropathy in both
a Greek and a US healthcare setting268. ACEI or ARB therapy was compared with alternative
treatment regimens that did not include these drugs. For patients receiving ACEI or ARBs, the
net cost saving was more than $2000 per patient in both settings, but these results were not
statistically significant and there was heterogeneity between trials. The study demonstrates that
treating patients with diabetic nephropathy with agents that block the renin-angiotensin system
as part of the treatment regimen is cost effective, resulting in a 23% reduction in the incidence
of ESRD and in net cost savings for the insurance system organisations.
Conclusion
All of the economic evaluations found that these drugs confer both health gains and net cost
savings compared with conventional (non-ACE inhibitor) therapy, ie they are dominant therapies.
9.2.6
121
The GDG agreed that the evidence of benefit of ACEI/ARBs in people with diabetes and microor macroalbuminuria was strong.
RCTs and meta-analyses of RCTs that have analysed cardiovascular outcomes in patients with
CKD/proteinuria treated with renin-angiotensin blockade have shown significant reduction in
cardiovascular outcomes in both diabetic nephropathy and nondiabetic nephropathy. Benefits
in terms of reduction in proteinuria and reduction in progression of CKD have also been
shown. Renin-angiotension blockade confers benefit in reducing adverse cardiovascular events
in patients with proteinuria when compared with control therapy; a similar benefit is seen in
reducing the risk for heart failure in diabetic nephropathy and total cardiovascular outcomes in
nondiabetic nephropathy patients. These results might suggest that renin-angiotensin system
blockade may be more beneficial in CKD patients with proteinuria.
On the basis of the evidence, the GDG agreed that the threshold level of proteinuria at which
ACEI/ARBs should be recommended in people without diabetes or hypertension was an ACR
70 mg/mmol or PCR 100 mg/mmol (approximately equivalent to urinary protein excretion
of 1 g/day). The threshold level of proteinuria at which ACEI/ARBs should be recommended
in people without diabetes with hypertension was an ACR of 30 mg/mmol or PCR
50 mg/mmol (approximately equivalent to urinary protein excretion of 0.5 g/day).
It is possible that ACEI/ARB therapy in people with CKD without diabetes and with lower levels
of proteinuria may also be beneficial but there is no evidence in this group at present. The GDG
agreed that clinical trials examining the effects in these people were needed as a matter of urgency
The GDG agreed that there was no evidence to suggest an advantage of one particular ACE
inhibitor over and above another or of ARB over and above an ACE inhibitor. There was also
no evidence to suggest increased effectiveness of combining an ACE inhibitor with an ARB over
and above the maximum recommended dose of each individual drug. However, the health
economic evidence suggested increased cost-effectiveness for ACEIs versus ARBs, indicating an
ACE inhibitor should first be prescribed, switching across to an ARB if the ACEI is not tolerated
due to non-renal side affects.
122
9.2.7
RECOMMENDATIONS
R41
When implementing blockade of the renin-angiotensin system, start treatment with an ACE
inhibitor first then move to an ARB if the ACE inhibitor is not tolerated.
R42
Offer ACE inhibitors/ARBs to people with diabetes and ACR more than 2.5 mg/mmol (men) or
more than 3.5 mg/mmol (women) irrespective of the presence of hypertension or CKD stage.
R43
Offer ACE inhibitors/ARBs to non-diabetic people with CKD and hypertension and ACR
30 mg/mmol or more (approximately equivalent to PCR 50 mg/mmol or more, or urinary
protein excretion of 0.5 g/24 h or more).
R44
Offer ACE inhibitors/ARBs to non-diabetic people with CKD and ACR 70 mg/mmol or more
(approximately equivalent to PCR 100 mg/mmol or more, or urinary protein excretion 1 g/24 h
or more), irrespective of the presence of hypertension or cardiovascular disease.
R45
Offer non-diabetic people with CKD and hypertension and ACR less than 30 mg/mmol
(approximately equivalent to PCR less than 50 mg/mmol, or urinary protein excretion less
than 0.5 g/24 h) a choice of antihypertensive treatment according to the NICE guidance on
hypertension (NICE clinical guideline 34) to prevent or ameliorate progression of CKD.
R46
When using ACE inhibitors/ARBs, titrate them to the maximum tolerated therapeutic dose
before adding a second-line agent.*
R47
To improve concordance, inform people who are prescribed ACE inhibitors or ARB therapy
about the importance of:
G
achieving the optimal tolerated dose of ACE inhibitor/ARB, and
G
monitoring eGFR and serum potassium in achieving this safely.
9.3
9.3.1
Clinical introduction
Reviews conducted across disease areas and countries suggest that 3050% of prescribed
medication is not taken as recommended. Adverse effects, poor instructions and poor
communication between healthcare professional and patient all contribute, particularly where
the tablet burden is high as is frequently the case in people with CKD. Nevertheless, the benefits
of ACEI/ARBs in prevention of progression of CKD in people with diabetes and proteinuric
kidney disease are clear, as are their benefits to people with heart failure and reduced left
ventricular function. Whilst rare complications such as anaphylaxis and angioedema are absolute
contraindications to ACEI/ARB therapy, and symptomatic hypotension and severe aortic stenosis
may also preclude their use, some contraindications may be more perceived than real.
Physicians may be reluctant to prescribe ACEI/ARBs in people with reduced GFR,
hyperkalaemia, and non-critical renal artery stenosis. A rise in serum creatinine concentration
and fall in GFR should be expected following introduction of treatment with ACEI/ARBs and
hyperkalaemia is a known complication of treatment.269,270 The incidence of hyperkalaemia
with ACEI/ARB treatment is low in those with normal renal function but obviously increases
as GFR falls. However, changes in serum creatinine and potassium concentrations to lesser or
greater degrees variably influence physicians in their approach to continuing treatment. What
one physician perceives as an intolerable fall in GFR or rise in potassium may not be interpreted
as such by another. Furthermore, changes in GFR and potassium during treatment with
ACEI/ARBs may be significantly influenced by a persons volume status, degree of sodium
depletion, and concurrent medications. Many people intolerant of ACEI/ARB treatment may
be successfully treated once these factors have been addressed. Educating the healthcare
community about these relative contraindications, and clearly stating what parameters should
be monitored, how often these parameters should be monitored, and what levels are acceptable,
could significantly affect outcomes in many people who might otherwise not be treated with
ACEI/ARBs (and also help avoid unwanted complications).
Concordance with agreed treatment plans is of obvious importance and the overall medication
burden faced by some patients is a consideration taken into account as part of good medical
practice.
There is insufficient evidence to recommend the routine use of spironolactone in addition to ACE inhibitor
and ARB therapy to prevent or ameliorate progression of CKD.
123
9.3.2
In adults with CKD upon commencing an ACE inhibitor or ARB, what parameters of renal
function should be monitored and how often? (What action threshold should be used for
stopping treatments with an ACE inhibitor/ARB)?
Methodology
There were several studies that showed that serum creatinine and potassium levels increase
upon treatment with ACE inhibitors, however, analysis of the clinical impact of these changes
(for example, occurrence of acute renal failure) was lacking, and thus, did not address the
question.
One systematic review (12 studies, N=1102 randomised to ACE inhibitors, mean follow-up
3.2 years)269 examined the changes in serum creatinine and potassium in people with >25%
loss of renal function upon commencement of ACE inhibitors. The authors presented an
algorithm for monitoring serum creatinine and potassium levels in people commencing ACE
inhibitors.
9.3.3
9.3.4
s
Evidence statements
Serum creatinine levels
Initiation of ACE inhibitor or ARB is associated with a 30% increase in serum creatinine levels
above baseline. This increase will occur within the first 2 weeks of treatment and usually
stabilises within 2 to 4 weeks. In 11 studies (N not given), the GFR decline was slower at the end
of the study than after initiation of ACEI therapy. (Level 1+)
In 2 long-term studies in diabetic CKD populations, (N=65) initiation of ACE inhibitor
treatment resulted in a 39% reduction in GFR from baseline. After 6 years of therapy, the GFR
returned to levels not significantly different from baseline within 1 month of stopping ACE
inhibitor treatment. (Level 1+)
There were limited data on the benefit of ACE inhibitors in advanced disease (GFR <30 ml/min).
(Level 1+)
124
9.3.5
9.3.6
RECOMMENDATIONS
R48
In people with CKD, measure serum potassium concentrations and estimate the GFR before
starting ACEI/ARB therapy. Repeat these measurements between 1 and 2 weeks after starting
ACEI/ARB therapy and after each dose increase.
R49
ACEI/ARB therapy should not normally be started if the pre-treatment serum potassium
concentration is significantly above the normal reference range (typically >5.0 mmol/l).
R50
R51
R52
Stop ACEI/ARB therapy if the serum potassium concentration rises to above 6.0 mmol/l and
other drugs known to promote hyperkalaemia have been discontinued.
125
R53
Following the introduction or dose increase of ACEI/ARB, do not modify the dose if either
the GFR decrease from pre-treatment baseline is <25% or the plasma creatinine increase from
baseline is <30%.
R54
If there is a fall in eGFR or rise in plasma creatinine after starting or increasing the dose of
ACEI/ARB, but it is less than 25% (eGFR) or 30% (serum creatinine) of baseline, the test
should be repeated in a further 12 weeks. Do not modify the ACE/ARB dose if the change in
eGFR <25% or change in plasma creatinine is <30%.
R55
9.4
9.4.1
Clinical introduction
Although there is much clinical evidence to support the use of ACE inhibitors and ARBs to
delay progression of chronic kidney disease, few studies include older people with CKD in the
study population. The older population are also more prone to reduced volume status and
sodium depletion, have greater comorbidity and are more likely to be taking concurrent
medications making them potentially more susceptible to the adverse effects of ACEI/ARBs.
Indeed, there is a perception that ACEI or ARB treatment puts the older person at greater risk
for adverse events such as acute kidney failure/injury, hypotension, falls, and reduced quality of
life. Few studies have described the progression of CKD in older community based individuals,
and none have confirmed the widely held belief that low GFR is associated with a rapid
progression of kidney dysfunction in older people.161,271 Should we reconsider the role of
renin-angiotensin system blockade to prevent progression of CKD in the context of the older
population in which the burden of overt proteinuric nephropathies is believed to be lower than
in other populations?
Is there a greater potential risk of further deterioration of renal function because of the high
prevalence of renal stenotic atherosclerotic lesions and very frequent concomitant use of
diuretics and nonsteroidal anti-inflammatory drugs?
9.4.2
Methodology
An open-label RCT conducted in Japanese adults with nondiabetic, hypertensive renal disease
(N=141, age range 6075 years, mean age 67, mean follow-up 3.1 years) compared the effect of
an ARB (candesartan) with conventional antihypertensive treatment on cardiovascular events
in those with and without a previous history of cardiovascular disease.272 This small, open-label
RCT was terminated after 3 years, due to the increasing prevalence of ARBs as physicians were
switching from conventional treatment to ARBs.
126
One post-hoc analysis of the RENAAL trial (N=1513, mean follow-up 3.4 years) examined the
effect of increasing age on the efficacy and safety of losartan versus placebo (conventional
antihypertensive treatment).273 The trial participants had type 2 diabetes with nephropathy
and were stratified by age: 57 years (N=505), age >57 to 65 years (N=587), and age >65 years
(N=421). Although this study lacked the statistical power necessary to assess efficacy of losartan
treatment in each of the three increasing age ranges, it did analyse the interaction between age
and losartan treatment for the outcomes of death, hyperkalaemia, and adverse events such as
acute renal failure. The oldest participant in the study was 74 years old, and thus this study lacks
data on very elderly people.
A retrospective cohort analysis of people >65 years of age was conducted to investigate whether
receiving an ACE inhibitor at hospital discharge following an acute myocardial infarction
increased one year survival rates in people with poor renal function (serum creatinine >3 g/dl,
N=1582) compared with people with better renal function (serum creatinine 3 mg/dl,
N=19,320).274 This study was limited by lacking data on protein excretion rate and the use of
serum creatinine alone as an indicator of renal function.
9.4.3
9.4.4
s
Evidence statements
All-cause mortality
The treatment effect of losartan on risk of death in a population with diabetic nephropathy did
not significantly differ by age (p=0.695 adjusted for treatment group, region, proteinuria,
albumin, creatinine, haemoglobin). In all three age groups (people 57 years, age >57 to 65 years,
or >65 years) there was NS difference in risk of death between losartan and placebo.273 (Level 2+)
In a nondiabetic Japanese population with renal disease (N=141), no deaths occurred in the
people without a past history of cardiovascular disease (treated with candesartan or
conventional therapy).
G
Four deaths occurred in the group with a past history of CVD treated with candesartan.
G
Four deaths occurred in the group with a past history of CVD treated with conventional
therapy (p value not stated).272 (Level 1+)
Stroke
In people with nondiabetic, hypertensive renal disease, with or without a previous history of
CVD, there was NS difference between candesartan and conventional treatment for the
incidence of stroke.272 (Level 1+)
Hyperkalaemia
Losartan was associated with a greater rate of hyperkalaemia. This effect was present in all age
ranges. Thus, increasing age did not significantly increase the risk of hyperkalaemia from
losartan.273 (Level 2+)
9.4.5
128
9.4.6
RECOMMENDATION
R56
Where indicated, the use of ACEI/ARBs should not be influenced by a persons age as there is
no evidence that their appropriate use in older people is associated with a greater risk of
adverse effects.
9.5
9.5.1
Clinical introduction
Aldosterone is thought to contribute to progressive renal disease. Studies in experimental rat
models showed that aldosterone may contribute to the progression of kidney disease and
antagonists of aldosterone may reduce proteinuria and retard the progression of kidney disease
independently of effects on blood pressure.275,276 Plasma aldosterone level was shown to correlate
with the rate of progression of kidney disease and the increase in rate of kidney disease
progression caused by high protein intake was attributable in part to aldosterone.277279
Although ACEI/ARBs inhibit the renin-angiotensin system, they do not efficiently decrease
plasma aldosterone. Haemodynamic and humoral actions of aldosterone have important clinical
implications for the pathogenesis of progressive renal disease and consequently may influence
future antihypertensive strategies. Although ACEI/ARBs are effective in preventing disease
progression, there may be additional benefit from concurrent aldosterone-receptor blockade.280
To date there has been limited research into the use of spironolactone, an aldosterone receptor
antagonist, to reduce aldosterone escape during treatment with ACEI/ARBs in adults with CKD.
9.5.2
In adults with proteinuric or non-proteinuric CKD, does treatment with (a) spironolactone
alone, (b) combinations of spironolactone and ACE inhibitors, (c) combinations of
spironolactone and ARBs, or (d) combinations of spironolactone and ACE inhibitors and
ARBs decrease mortality and reduce the risk of progression of CKD compared with
placebo or other antihypertensive agents?
Methodological introduction
There were no studies in a CKD population that compared spironolactone with alpha- or betablockers, calcium channel blockers, or diuretics. There were no studies that investigated
spironolactone in adults with non-proteinuric CKD.
Three double-blind RCTs examined the effects of spironolactone in addition to treatment with
ACE inhibitors and/or ARBs in adults with diabetic nephropathy281,282 and in a mixed
population of diabetic and nondiabetic nephropathy.283 One open label randomised study
compared the addition of spironolactone to conventional ACEI and ARB therapy with
conventional therapy alone in nondiabetic adults with proteinuric CKD.284 One study that
compared spironolactone with cilazapril (ACEI) in a diabetic population with proteinuric
nephropathy was excluded because it lacked intention-to-treat analysis, and concealment and
blinding were not stated.285
The results of these studies should be viewed with caution as the sample sizes were small
(N=21165) and duration of these trials (2 months1 year) was short. None of the studies
reported cardiovascular outcomes, mortality, or progression to ESRD.
9.5.3
129
9.5.4
s
Evidence statements
Renoprotective effects of spironolactone: reduction in proteinuria or albuminuria
In two RCTs conducted in diabetic adults with nephropathy concomitantly treated with ACE
inhibitors or ARBs, spironolactone significantly reduced albuminuria compared with
placebo.281,282 (Level 1+)
In a nondiabetic CKD population, addition of spironolactone to ACEI or ARB therapy resulted
in a significant reduction in proteinuria. The reduction in proteinuria was significantly greater
in people with GFR <60 ml/min/1.73 m2 than in people with GFR >60 ml/min /1.73 m2. By
contrast, proteinuria did not change from baseline in people treated with ACEI or ARB therapy
alone.284 (Level 1+)
In an RCT conducted in a mixed diabetic/nondiabetic mixed CKD population, the reduction in
24-hour proteinuria was significantly greater in either the ramipril + spironolactone group or in
the ramipril + irbesartan + spironolactone group, compared to the ramipril group. Compared
with the ramipril + irbesartan group, there was a greater reduction in 24-hour proteinuria in the
ramipril + irbesartan + spironolactone group. There was NS difference in proteinuria reduction
between ramipril + spironolactone group and ramipril + irbesartan + spironolactone groups. The
spironolactone-induced decrease in proteinuria was similar regardless of presence of diabetes.283
(Level 1+)
Change in GFR
In three studies,281,283,284 there was no significant difference in GFR decline in patients
receiving spironolactone with ACEI or ARB therapy compared to the control (placebo or no
treatment). (Level 1+)
By contrast, van den Meiracker et al. reported that spironolactone significantly decreased the
eGFR compared to placebo. (Level 1+)
130
9.5.5
131
In adults with CKD and proteinuria, do statins decrease proteinuria and decrease the risk of
progression of CKD compared with other treatments or placebo?
10.1.2 Methodology
There were no trials of statins versus other antilipemic agents such as fibrates or fish oils. No
trials addressed clinically relevant markers of renal progression such as doubling of serum
creatinine or time to ESRD.
Three meta-analyses assessed the efficacy of statins compared to placebo in decreasing the risk
of renal disease progression in adults with CKD.
The meta-analysis by Douglas et al. (15 RCTs, N=1384, mean follow-up 6 months)289
investigated the effect of statins on changes in proteinuria. Study heterogeneity was mostly
avoided by stratifying the data by baseline levels of proteinuria. The limitations with this metaanalysis were that the individual studies were few, small and methodologically limited.
The meta-analysis by Sandhu et al. (27 RCTs, N=39704, mean follow-up 1 year)290 measured
the effect of statins compared to control on the rate of change of GFR and on changes in
proteinuria in populations with diabetic or hypertensive renal disease or in people with
glomerulonephritis. While this meta-analysis included the studies in the Douglas et al. metaanalysis, the between-study heterogeneity was very high. The pooled analysis of changes in
proteinuria or albuminuria was particularly marred by significant heterogeneity. However, the
analysis of changes in GFR was an important outcome, and was not reported in the Douglas
et al. 2006 meta-analysis.
A systematic review assessed cardiovascular outcomes, changes in GFR and 24-hour proteinuria
in people with CKD randomised to statins or placebo/no treatment (50 studies, N=30,144,
133
follow-up ranged from 260 months).291 Subgroup analysis was performed in people with predialysis CKD (26 studies), people undergoing dialysis (11 studies) and renal transplant
recipients (17 studies).
The effects of statins versus placebo on renal disease progression in adults with varying severity
and different causes of CKD are summarised in Table 10.1, at the end of the evidence
statements.
Changes in GFR
Overall, statins did not significantly slow decline in GFR. There was significant heterogeneity in
the meta-analyses for this outcome.290,291 (Level 1+)
Change in proteinuria
Statins significantly reduced proteinuria compared to placebo in people with CKD and baseline
proteinuria 30299 mg/day.289 (Level 1++)
Statins significantly reduced proteinuria compared with placebo; however there was significant
heterogeneity in this analysis.291 (Level 1++)
By contrast, the meta-analysis of Sandhu et al. showed NS effect of statins on proteinuria.
However, there was significant between-study heterogeneity in this analysis. (Level 1+)
Table 10.1 Effect of statins versus placebo on changes in GFR and proteinuria in adults with CKD
Study
CKD population
Change in GFR
290
NS*
NS*
NS
NS *
289
291
134
Change in proteinuria
NS*
135
The optimal targets for plasma lipids in people with CKD are not yet known. Statins are effective
at lowering total and low-density lipoprotein (LDL)-cholesterol and fibrates reduce plasma
triglyceride concentrations and raise HDL-cholesterol. Nicotinic acid appears most suited to the
dyslipidaemia of CKD because it raises HDL-cholesterol, lowers lipoprotein (a), reduces
triglycerides and shifts the LDL-cholesterol fraction to less atherogenic particles. SIGN guidelines
recommend treatment with statins for people with stage 13 CKD and a predicted 10 year
cardiovascular risk of 20%, irrespective of baseline lipid parameters. The CARI guidelines
suggest that statins may retard progression of renal failure but make no specific recommendation.
The UK CKD guidelines recommend that people with CKD and coronary disease should be
treated according to existing guidelines and those who do not have evidence of coronary disease
should be treated according to their estimated risk, using the Joint British Societies Guidelines
(recognising that these guidelines specifically exclude CKD from their remit).
In adults with CKD and dyslipidaemia, do lipid lowering agents (statins, fibrates, fish oils)
decrease cardiovascular disease risk and all cause mortality compared with placebo or
each other?
10.2.2 Methodology
Hydroxymethyl glutaryl CoA reductase inhibitors (statins), fibric acid derivates (fibrates), and
omega-3 fatty acids (fish oils) are antilipemic therapies that may reduce the risk of
cardiovascular disease by decreasing triglyceride or LDL cholesterol levels and increasing HDL
cholesterol levels. There were very few trials of antilipemic therapies in non-dialysis CKD
populations. There were no head-to-head studies of the three antilipemic therapies in adults
with CKD. There were no studies that examined the efficacy of omega-3 fatty acids to reduce
the risk of cardiovascular disease in adults with CKD.
A post-hoc analysis of the Veterans Affairs High-Density Lipoprotein Intervention RCT
(VA-HIT: N=1046, follow-up 5.3 years),301 compared a fibrate (gemfibrozil) to placebo for
cardiovascular outcomes in men with a history of coronary heart disease and creatinine
clearance <75 ml/min. This study is limited by a lack of baseline proteinuria data, all the
participants were men and the population did not include people with severe renal disease.
Creatinine clearance overestimates GFR and it is likely that the participants identified as having
chronic renal insufficiency could have had lower renal function than estimated. Also, the
creatinine concentrations were not standardised between centres or calibrated against a
reference standard.
A systematic review assessed cardiovascular outcomes, changes in GFR and 24-hour proteinuria
in people with CKD randomised to statins or placebo/no treatment (50 studies, N=30,144,
follow-up ranged from 260 months).291 Subgroup analysis was performed in people with predialysis CKD (26 studies), people undergoing dialysis (11 studies) and renal transplant
recipients (17 studies).
A post-hoc analysis of the Scandinavian Simvastatin Survival RCT (4S: N=2314, follow-up
5.5 years, mean age 60 years) compared cardiovascular outcomes in people with coronary heart
disease, raised cholesterol, and GFR <60 ml/min/1.73 m2 randomised to placebo or
simvastatin. This study lacked proteinuria data and cause of CKD. Estimated, rather than
measured, GFR was used to assess renal function.302
136
137
There were NS differences between statins and placebo for stroke.302 (Level 1+)
Adverse events
Rates of discontinuation of study drug therapy because of adverse events were similar in
simvastatin and placebo groups.302 (Level 1+)
Table 10.2 Effect of statins versus placebo on cardiovascular outcomes in adults with CKD
Study
Population
Outcome
N total
participants
291
18,781
302
2,314
Not applicable
302
508
HR 1.232 (1.0241.117)
[sic] NS [sic]
Not applicable
291
Cardiovascular
mortality
18,085
0
NS
291
Non-fatal
cardiovascular
events
19,363
HR 0.851 (0.9211.128)
[sic] NS
30.7
NS
302
Major coronary
events
508
Not applicable
302
Major coronary
events
2,314
Not applicable
Effect size
Heterogeneity
(% I2)
138
table should be used for people with diabetes.29 It was further recommended that studies are
needed to assess the effect of CKD on cardiovascular risk.
On the basis of the evidence of effect in secondary prevention of cardiovascular disease the
GDG recommended that lipid lowering therapy should be prescribed in people who have
experienced a cardiovascular event. The evidence showed that there was benefit from statins in
all people not just those with elevated lipid concentrations.
The lack of statistically significant differences observed in subgroup analyses may due to the
small numbers of people in these groups and the consequent lack of statistical power.
The GDG noted that there is a large international multicentre trial in progress which addresses
the effects of lipid lowering with simvastatin and ezetimibe on outcomes in people with CKD
without established coronary heart disease.
The GDG concluded that there was no evidence that statins had detrimental effects on kidney
function in people with CKD, but it was noted that there appeared to be an increase in
creatinine concentrations in people prescribed fibrates.
10.2.6 RECOMMENDATIONS
R57
The use of statin therapy for the primary prevention* of CVD in people with CKD should not
differ from its use in people without CKD and should be based on existing risk tables for
people with and without diabetes. It should be understood that the Framingham risk tables
significantly underestimate risk in people with CKD.
R58
Offer statins to people with CKD for the secondary prevention of CVD irrespective of
baseline lipid values
There is insufficient evidence to support the routine use of statins to prevent or ameliorate progression of
CKD.
The use of statins for the primary prevention of CVD in people with CKD should be informed by the Study
of Heart and Renal Protection (SHARP) reported in: Baigent C, Landry M. Study of heart and renal protection.
Kidney International (2003); 63: S207S210.
139
CKD is an independent risk factor for the development of generalised atherosclerosis and
coronary artery disease, and is associated with a worse prognosis following cardiovascular events.
People with CKD have a higher risk of morbidity and death related to cardiovascular disease than
of progression to end stage renal failure. Large clinical trials in the general population have
demonstrated that antiplatelet agents reduce the risk of cardiovascular events, and may improve
patency rates following revascularisation therapy. What evidence is there that the benefits of
antiplatelet therapy in people with CKD outweigh the potential risks of bleeding complications?
10.3.2 Methodology
There were very few studies conducted in populations with non-ESRD CKD that assessed the
safety and efficacy of antiplatelet agents (aspirin, clopidogrel, dipyramidole, glycoprotein
IIb/IIIa inhibitors). There were no studies that investigated anticoagulants (warfarin) to prevent
mortality and cardiovascular events in people with CKD.
One post hoc analysis of the double blind Clopidogrel in Unstable Angina to Prevent Recurrent
Events RCT (CURE, N=12,253, mean follow-up 9 months) compared clopidogrel with placebo
in patients with various levels of renal dysfunction and non-ST-segment elevation acute
coronary syndrome (NSTEACS). Both trial arms received aspirin (75325 mg/day).310
Three cohort studies investigated the effect of prescription of aspirin compared with nonprescription of aspirin on mortality in people with CKD and heart failure (HF) and coronary
artery disease (CAD) (N=6427, 1 year follow-up)311 or in people with acute MI and
CKD (N=1342, 9.8 months follow-up)312 or in people with ACS and CKD (N=5549, 2 year
follow-up).122
One cohort study investigated the effect of non-prescription of any antiplatelet agent (aspirin,
clopidogrel, dipyridamole, or ticlopidine) on mortality within 6 months of hospital discharge
in men with CKD undergoing coronary artery bypass grafting (CABG) (N=19,411).313
Renal function assessment was limited to one measurement of serum creatinine upon hospital
admission in all of the cohort studies. The cohort studies are also limited by lack of data on
treatment adherence.
The effect of antiplatelet agents on mortality, cardiovascular events, and adverse events in
people with CKD and various baseline cardiovascular comorbidities is summarised in Table
10.2, at the end of the evidence statements.
140
Table 10.3 The effect of antiplatelet agents on mortality, cardiovascular events, and adverse events in
people with CKD and various cardiovascular comordbitities (95% CI)
Reference
Comparison
Population
Outcome
Effect size
310
4,087
All-cause mortality
RR 0.95 (0.781.16) NS
310
4,075
All-cause mortality
RR 0.91 (0.681.21) NS
122
306
All-cause mortality
HR 1.232 (1.0241.117),
p not stated
122
1,795
All-cause mortality
HR 1.029 (0.9881.081)
NS
continued
141
Table 10.3 The effect of antiplatelet agents on mortality, cardiovascular events, and adverse events in
people with CKD and various cardiovascular comordbitities (95% CI) continued
Reference
Comparison
Population
Outcome
Effect size
122
2,018
All-cause mortality
HR 0.851 (0.9211.128)
NS
312
Aspirin versus no
cardioprotective agents* at
hospital discharge
70
All-cause mortality
HR 0.21 (0.080.53),
p not stated
312
Aspirin versus no
cardioprotective agents* at
hospital discharge
412
All-cause mortality
HR 0.65 (0.371.12) NS
312
Aspirin versus no
cardioprotective agents* at
hospital discharge
612
All-cause mortality
HR 0.97 (0.501.86) NS
311
466
1 year All-cause
mortality
HR 0.84 (0.641.11) NS
311
2,047
1 year All-cause
mortality
HR 0.81 (0.670.98),
p not given
313
Non-prescription of
antiplatelet drugs** within
6 months of hospital
discharge
3,260
All-cause mortality
within 6 months of
hospital discharge
OR 1.90 (1.232.94),
p=0.004
310
4,087
310
4,075
310
4,087
Cardiovascular death
RR 0.95 (0.771.17) NS
310
4,075
Cardiovascular death
RR 0.85 (0.631.16) NS
310
4,087
310
4,075
310
4,087
Major bleed
RR 1.37 (0.892.12) NS
310
4,075
Major bleed
RR 1.78 (0.953.34) NS
310
4,087
Minor bleed
RR 1.50 (1.211.86),
p<0.05
310
4,075
Minor Bleed
RR 1.61 (1.272.06),
p <0.05
142
10.3.6 RECOMMENDATION
R59
Offer antiplatelet drugs to people with CKD for the secondary prevention of CVD. CKD is
not a contraindication to the use of low dose aspirin but clinicians should be aware of the
increased risk of minor bleeding in people with CKD given multiple antiplatelet drugs.
143
11 Asymptomatic hyperuricaemia
11.1 Asymptomatic hyperuricaemia in people with CKD
11.1.1 Clinical introduction
Uric acid is a product of purine metabolism. After glomerular filtration, uric acid is both
reabsorbed and excreted in the proximal tubule. Hyperuricaemia may result from either increased
production or decreased excretion of uric acid. Increased production may occur through enzyme
defects, increased purine turnover (myeloproliferative disorders and certain forms of cancer), or
from increased consumption in diet. In patients with renal disease there is decreased urinary uric
acid excretion. Whether this gives rise to hyperuricaemia depends on the degree of gastrointestinal excretory compensation.314 It has been shown that increasing levels of uric acid are
associated with significantly increased hazard ratios for CKD, but the associations with
progressive CKD are less strong.315,316
There is theoretical evidence to support the role for uric acid as both an initiator of CKD, and a
factor involved in its progression. It has been proposed that an elevated uric acid may have a role
in initiating hypertension, arteriolosclerosis, kidney disease, insulin resistance, and hypertriglyceridaemia. Once renal microvascular disease develops, the kidney will drive hypertension;
once obesity develops fat-laden adipocytes will contribute to insulin resistance, and once kidney
disease develops the kidney will also drive progression.317
Allopurinol decreases serum uric acid levels by inhibiting the enzyme xanthine oxidase.
Experimental rat models have suggested that allopurinol treatment can prevent hyperuricaemiainduced functional and structural injury of the kidney. In animal models of established renal
diseases, correction of the hyperuricemic state can significantly improve blood pressure control,
decrease proteinuria, and decrease the amount of glomerulosclerosis, tubulointerstitial fibrosis,
and vasculopathy.318320
Does lowering uric acid with (a) allopurinol, (b) uricosuric agents (probenecid,
sulfinpyrazone), (c) rasburicase (urate oxidase), decrease morbidity and mortality in adults
with CKD and hyperuricaemia?
11.1.2 Methodology
In non-CKD populations, treatment of hyperuricaemia is only indicated if the patient has
symptomatic arthritis. The literature was reviewed to determine if treatment with allopurinol,
probenecid, sulfinpyrazone, or rasburicase decreases progression of CKD and mortality in
people with CKD and hyperuricaemia. There was little evidence in this area. There were no
studies assessing rasburicase, probenecid, or sulfinpyrazone in people with pre-dialysis CKD.
Only one open label RCT321 compared 12 months of allopurinol treatment (100200 mg/day
dose, N=25) with usual treatment (N=26) in adults (mean age 48 years) with CKD and
hyperuricaemia. Both trial arms received lipid lowering and antihypertensive agents
throughout the study. This study was excluded as it had several methodological limitations. It
was a small study, open-labelled, did not present intention to treat analysis, and did not provide
145
statistical power calculations. There was little information on what treatments the usual
treatment group received. It may be also be difficult to extrapolate the findings from this study
to a UK population as it was conducted in a Chinese population.
11.1.6 RECOMMENDATION
R60
146
There is insufficient evidence to recommend the routine use of drugs to lower uric acid in
people with CKD who have asymptomatic hyperuricaemia.
IgA nephropathy
Alports syndrome
Trauma
In the absence of a urological cause, haematuria can be presumed to be coming from the
kidneys, most commonly as a result of one of the nephrological diseases listed above. However
a firm diagnosis of most of these conditions (except the cystic diseases which are generally
diagnosed radiologically) would require a kidney biopsy. This section is concerned with isolated
invisible haematuria. This implies that at presentation there is no associated proteinuria, and
that the GFR is normal (or if impaired there is no retrospective evidence of progressive loss of
GFR). The challenge therefore is to decide a) how far to investigate the cause, and b) how people
with isolated invisible haematuria should be monitored in the long term.
12.1.2 Methodology
Isolated invisible haematuria is defined as 3 erythrocytes per high power field in the urine
without any other urine abnormalities (absence of infection or proteinuria). The clinical
significance of isolated invisible haematuria was assessed with respect to morbidity and
progression of CKD (declining GFR, development of proteinuria, progression to ESRD).
147
One prospective case series assessed renal functional decline in Japanese men (N=404) with
confirmed isolated invisible haematuria (+1 result on a reagent strip and >5 RBC/hpf by
microscopy) identified in a mass population screening between 1983 and 1996 in Hitachi,
Japan, for a mean follow-up of 6.35 years.322
Development of proteinuria
In a case series, 9% of men with asymptomatic invisible haematuria developed proteinuria
(defined as chronic nephritic syndrome) during follow-up.322 (Level 3)
12.1.6 Recommendations
148
R61
When there is the need to differentiate persistent invisible haematuria in the absence of
proteinuria from transient haematuria, regard two out of three positive reagent strip tests as
confirmation of persistent invisible haematuria.
R62
Persistent invisible haematuria, with or without proteinuria, should prompt investigation for
urinary tract malignancy in appropriate age groups.
R63
13.1.2 Methodology
Serum calcium, phosphate, intact parathyroid hormone (iPTH), and vitamin D levels were
assessed in adults with various stages of CKD in five cross-sectional studies and one observational
study.
Two reports from the cross-sectional US NHANES III study (N=14,679) examined changes in
serum calcium and phosphate324 and 25-hydroxyvitamin D325 by level of renal function. Hsu
et al. also reported the prevalence of hyperphosphataemia.
A cross-sectional study compared levels of serum calcium, phosphate, iPTH, and vitamin D
amongst stage 3, 4, and 5 CKD. The prevalence of vitamin D deficiency, hyperphosphataemia,
and hypocalcaemia was examined in people with stages 3 and 4 CKD.326
A cross-sectional analysis of CKD patients (N=1836) was performed to ascertain levels of
serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D within
each stage of CKD.327
149
A cross-sectional analysis at baseline of the Study for the Evaluation of Early Kidney disease
participants (SEEK, N=1814, mean age 70 years)328 examined serum calcium, phosphate,
iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D within decreasing deciles of eGFR.
This study also reported the prevalence of abnormal calcium, phosphate, iPTH, and vitamin D
with decreasing eGFR.
All of these studies were limited by the use of one serum creatinine measurement to estimate
renal function.
GFR was measured by 99Tc-DTPA clearance in one small observational study and levels of serum
calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D in people with
mild CRF (N=27) or moderate CRF (N=12) were compared with healthy people (N=12).329
Calcium, phosphate, iPTH, and vitamin D levels with decreasing renal function are
summarised in Table 13.1 at the end of the evidence statements.
Serum calcium
Five studies showed that serum calcium levels decreased only in advanced renal disease. Two of
these studies reported the prevalence of hypocalcaemia in a CKD population.
Of people with GFR <20 ml/min, 15% had abnormal Ca levels (Ca <2.1 mmol/l).328 (Level 3)
43% of people with stage 3 CKD and 71% of people with stage 4 CKD had serum
Ca <2.37 mmol/l.326 (Level 3)
Two studies showed that people with stage 4 CKD had significantly lower serum calcium than
people with stage 3 CKD.326,327 (Level 3)
People with moderate CRF (GFR 2039 ml/min/1.73m2) had significantly lower Ca levels than
people with mild CRF (GFR 4090 ml/min/1.73m2).329 (Level 3)
Compared to men with CrCl >80 ml/min, men with CrCl <20 ml/min had a significant
decrease in ionised serum Ca.324 (Level 3)
Serum phosphate
Five studies showed that serum phosphate levels increased with advanced renal disease. Three
of these studies showed that abnormal phosphate levels were highly prevalent when eGFR was
<20 ml/min.
Of people with eGFR 2029 ml/min, 15% had abnormal phosphorus levels (P >1.49 mmol/l).
Of people with GFR <20 ml/min, 40% had abnormal phosphorus levels.328 (Level 3)
The prevalence of hyperphosphataemia (serum P >1.45 mmol/l) increased with declining CrCl:
7% of people with CrCl 2030 ml/min, and 30% of people with CrCl <20 ml/min had
hyperphosphataemia.324 (Level 3)
150
3% of people with stage 3 CKD and 22% of people with stage 4 CKD had serum
P >1.52 mmol/l.326 (Level 3)
Two studies showed that people with stage 4 CKD had significantly higher serum phosphate
levels than people with stage 3 CKD.326,327 (Level 3)
People with stage 5 CKD had significantly higher serum phosphate than people with stage 4
CKD.327 (Level 3)
Serum 1,25-dihydroxyvitamin D
Four studies reported decreases in 1,25-dihydroxyvitamin D in early stages of CKD.
23% of people with CRF were below the reference range of serum 1,25-dihydroxyvitamin D at
GFR <60 ml/min/1.73m2. People with mild CKD (GFR 4090 ml/min/1.73m2) had significantly
lower levels of 1,25-dihydroxyvitamin D compared with healthy people.329 (Level 3)
Deficiency of 1,25-dihydroxyvitamin D (<22 pg/ml) was seen as GFR decreased to approximately
45 ml/min/1.73 m2. The prevalence of 1,25-dihydroxyvitamin D deficiency was approximately
15%, 15%, 20%, 30%, 45%, 50%, and 65% in people with eGFR 7079, 6069, 5059, 4049,
3039, 2029, and <20 ml/min/1.73 m2, respectively.328 (Level 3)
Two studies showed that people with stage 4 CKD had significantly lower serum 1,25-dihydroxyvitamin D levels compared with people with stage 3 CKD.326,327 (Level 3)
Serum 25-hydroxyvitamin D
Two studies showed NS differences in serum 25-hydroxyvitamin D with worsening renal
function.327,329 (Level 3)
There was NS difference in serum 25-hydroxyvitamin D for people with GFR 3059 ml/min/
1.73 m2 compared with people with GFR 90 ml/min/1.73m2. Compared with people with GFR
90 ml/min/1.73 m2, people with GFR 1529 ml/min/1.73 m2 had significantly lower serum
25-hydroxyvitamin D.325 (Level 3)
Multiple regression analysis showed NS relationship between eGFR and serum 25-hydroxyvitamin D (p=0.8932). The prevalence of deficiency in serum 25-hydroxyvitamin D (<15 ng/ml)
151
remained stable until GFR <30 ml/min/1.73 m2, when the prevalence of serum 25-hydroxyvitamin D deficiency increased. The prevalence of serum 25-hydroxyvitamin D deficiency was
approximately 15%, 20%, and 25% in people with eGFR 3930, 2920, and <20 ml/min/1.73 m2,
respectively.328 (Level 3)
57% of people with stage 3 CKD and 58% of people with stage 4 CKD had serum 25-hydroxyvitamin D insufficiency (1030 ng/ml). 14% of people with stage 3 CKD and 26% of people
with stage 4 CKD had serum 25-hydroxyvitamin D deficiency (<10 ng/ml).326 (Level 3)
Table 13.1 Summary of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D
levels according to level of renal function (95% CI)
CKD stage 3a
(GFR
5945 ml/min/
1.73m2)
CKD stage 3b
(GFR
4430 ml/min/
1.73m2)
CKD stage 4
GFR
(2915 ml/min/
1.73m2)
CKD stage 5
(GFR
<15 ml/min/
1.73m2)
Reference
Serum parameter
327
1,836
Mean Ca
2.34 mmol/l;
N=354, p<0.05
326
201
Mean Ca
2.30 mmol/l,
N=113, p not
stated but
significant
329
51
Mean Ca
324
14,722 Change Ca
328
1,814
% Abnormal Ca
(Ca <2.1 mmol/l)
326
201
% Abnormal Ca
(Ca <2.37 mmol/l)
329
51
Mean phosphate
327
1,836
Mean phosphate
1.27 mmol/l,
N=354, p<0.05
vs. stage 3
1.58 mmol/l,
N=111,
p<0.05 vs.
stage 4
326
201
Mean phosphate
1.32 mmol/l,
N=113, p not
stated but
significant
1.42 mmol/l,
N=22, p not
stated but
significant
326
201
% Hyperphosphataemia
(P >1.52 mmol/l)
3%, N=65
22%, N=113
2.31 mmol/l;
GFR 4090 ml/min/
1.73m2, N=27
2.25 mmol/l,
N=22, p not
stated but
significant
1.0 mmol/l;
GFR 4090 ml/min/
1.73 m2, N=27
15%, GFR
<20 ml/min,
N=93
71%, N=113
continued
152
Table 13.1 Summary of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D
levels according to level of renal function (95% CI) continued
CKD stage 3a
(GFR
5945 ml/min/
1.73m2)
CKD stage 3b
(GFR
4430 ml/min/
1.73m2)
CKD stage 4
GFR
(2915 ml/min/
1.73m2)
CKD stage 5
(GFR
<15 ml/min/
1.73m2)
15%, GFR
2029 ml/min,
N=204
40%, GFR
<20 ml/min,
N=93
7% (95% CI
112%), CrCl
2030 ml/min,
N=224
30% (95% CI
062%), CrCl
<20 ml/min,
N=47
Reference
Serum parameter
328
1,814
% Hyperphosphataemia
(P >1.49 mmol/l)
324
14,722 % Hyperphosphataemia
(P >1.45 mmol/l)
329
51
Mean iPTH
327
1,836
Mean iPTH
16.47 pmol/l,
N=354, p<0.05
24.29 pmol/l,
N=111, p<0.05
326
201
Mean iPTH
235 pg/ml,
N=113, p not
stated but
significant
310 pg/ml,
N=22, p not
stated but
significant
328
1,814
% Hyperparathyroidism
(iPTH >65 ng/ml)
85%, GFR
<20, N=93
329
51
Mean 1,25dihydroxyvitamin D
327
1,836
Mean 1,25dihydroxyvitamin D
16.8 pg/ml,
N=156, p<0.05
vs. stage 3
13.2 pg/ml,
N=43, p<0.05
vs. stage 4
326
201
Mean 1,25dihydroxyvitamin D
62.3 pmol/l,
N=108, p not
stated but
significant
54.3 pmol/l,
N=20, p not
stated but
significant
328
1,814
% 1,25dihydroxyvitamin D
deficiency
(<22 pg/ml)
3% (95% CI 16%),
CrCl 3040 ml/min,
N=614
continued
153
Table 13.1 Summary of serum calcium, phosphate, iPTH, 1,25-dihydroxyvitamin D, and 25-hydroxyvitamin D
levels according to level of renal function (95% CI) continued
Serum parameter
CKD stage 3a
(GFR
5945 ml/min/
1.73m2)
CKD stage 3b
(GFR
4430 ml/min/
1.73m2)
CKD stage 4
GFR
(2915 ml/min/
1.73m2)
Reference
325
327
1,836
Mean 25hydroxyvitamin D
329
51
Mean 25hydroxyvitamin D
328
1,814
% 25hydroxyvitamin D
deficiency (<15 ng/ml)
326
201
% 25hydroxyvitamin D
insufficiency
(1030 ng/ml).
57%, N=65
58%, N=113
326
201
% 25hydroxyvitamin D
deficiency (<15 ng/ml)
14%, N=65
26%, N=113
26.2 ng/ml,
N=115, NS
63.3 nmol/
lGFR 4090 ml/min/
1.73 m2, N=27
CKD stage 5
(GFR
<15 ml/min/
1.73m2)
23.4 ng/ml,
N=35, NS
154
benefit from treatment. On the basis of the evidence the GDG agreed that there was no
requirement to routinely measure serum PTH concentrations in people with stage 1, 2 and 3A
CKD and that it was not usually necessary to measure it in people with stage 3B CKD in the
absence of specific indications. Specific indications to measure serum PTH would include
unexplained hypercalcaemia and symptoms suggestive of hyperparathyroidism.
The prevalence of abnormally low vitamin D concentrations increased once the GFR fell below
45 ml/min/1.73 m2;328 however, there was no information in this study on the prevalence of low
vitamin D concentrations in the general population.
Most laboratories do not measure 1,25 dihydroxyvitamin D concentrations.
On the basis of the evidence the GDG agreed that there was no need to routinely measure serum
vitamin D concentrations in people with stage 1, 2 and 3A CKD and that it was not usually
necessary to measure it in people with stage 3B CKD except where there are specific indications
such as unexplained hypocalcaemia or symptoms suggestive of vitamin D deficiency.
Because of the increased prevalence of abnormal serum calcium, phosphate, PTH and vitamin
D concentrations in people with stage 4 and 5 CKD and the fact that these people may require
treatment for renal bone disease it was recommended that calcium, phosphate and PTH
concentrations should be measured in people with stage 4 and 5 CKD.
There was no evidence to guide a recommendation about how frequently the calcium,
phosphate, PTH and vitamin D concentrations should be measured in people with stage 4 and
5 CKD and the GDG agreed that this would be determined by the clinical circumstances.
13.1.6 RECOMMENDATIONS
R64
The routine measurement of calcium, phosphate, parathyroid hormone (PTH) and vitamin D
levels in people with stage 1, 2, 3A or 3B CKD is not recommended.
R65
Measure serum calcium, phosphate and PTH concentrations in people with stage 4 or 5 CKD
(glomerular filtration rate (GFR) <30 ml/min/1.73 m2). Determine the subsequent frequency
of testing by the measured values and the clinical circumstances. Where doubt exists seek
specialist opinion.
155
13.2.2 Methodology
There were very few papers that examined the effect of bisphosphonates on bone mineral
density (BMD) and fracture outcomes in a CKD population.
One open-label RCT was excluded due to limitations in randomisation.331
One RCT (N=38, 1 year follow-up) investigated the effects of risedronate with and without
vitamin D in people with CKD (mean eGFR 78 ml/min) with high dose corticosteroid-induced
bone loss.332 Corticosteroids are frequently used in the treatment of kidney disease and even at
low doses may cause osteoporosis and bone fractures. Limitations of this study include the
small sample size, although there was no loss to follow-up.
A meta-analysis of data from nine phase III trials (N=9883, 2 years follow-up, mean age 75 years)
investigated the effects of risedronate in osteoporotic women with varying levels of renal
function.333 Although this was not a systematic review and included only phase III trials, due to
lack of other evidence, this paper was included. 91% of the pooled cases had some degree of
renal impairment and the analyses were conducted in categories of patients with mild (CrCl
5080 ml/min), moderate (CrCl 3050 ml/min) or severe (CrCl <30 ml/min) renal dysfunction.
A post-hoc analysis of the Fracture Intervention Trial (FIT, N=6458, 3 year follow-up, mean age
68 years)334 investigated the effects of alendronate on BMD and fracture in osteoporotic
women with moderate/normal renal function (eGFR 45 ml/min, N=5877) or severe renal
dysfunction (eGFR <45 ml/min, N=581).
The safety and efficacy of bisphosphonates in preventing osteoporosis in people with CKD are
summarised in Table 13.2, at the end of the evidence statements.
156
Risedronate
Change in BMD
Combination therapy of risedronate (2.5 mg/day) and vitamin D together resulted in a
significant increase in BMD, whereas BMD significantly decreased in the vitamin D alone
group. There was a NS decline in BMD in the risedronate group. The difference between BMD
changes in the risedronate and vitamin D combination therapy group and the vitamin D alone
group were statistically significant.332 (Level 1+)
The mean percent increase from baseline to endpoint in BMD at the lumbar spine, femoral
neck and trochanter was significantly greater in the risedronate (5 mg/day) arm than in the
placebo arm in all mild, moderate and severe renal impairment subgroups, with the exception
of the femoral neck in the severe renal impairment subgroup.333 (Level 1+)
Fractures
In one RCT, no fractures occurred over 1 year of follow-up.332 (Level 1+)
The incidence of new vertebral fractures was significantly lower in the risedronate (5 mg/day)
group than placebo groups within mild, moderate and severe renal impairment subgroups.333
Within the risedronate treatment group, the incidence of new vertebral fractures was similar
across renal impairment subgroups (p=0.124). Within the placebo group, new vertebral fractures
increased significantly with increasing severity of renal impairment (p<0.001). (Level 1+)
Adverse events
There were no adverse events in any of the treatment arms in the Kikuchi et al. RCT. (Level 1+)
The incidence of overall, urinary and renal function related adverse events were similar between
risedronate (5 mg/day) and placebo groups in the subgroups of patients with severe, moderate
and mild renal impairment.333 (Level 1+)
Alendronate
Change in BMD
Alendronate increased BMD at the total hip, femoral neck and spine to a greater extent in
postmenopausal women with eGFR <45 ml/min, than in women with eGFR 45 ml/min. There
was a significant interaction between renal function and the increase in total hip BMD
(p=0.04). Among women with osteoporosis (N=3214), alendronate produced a greater increase
in BMD at the hip and femoral neck in the group with eGFR <45 ml/min than women with
eGFR 45 ml/min. However at the spine the increase in BMD was greater in women with
eGFR 45 ml/min. There was no significant interaction between renal function and increase in
BMD.334 (Level 1+)
157
Fractures
Overall, alendronate significantly reduced the risk of clinical fractures (OR 0.8, 95% CI 0.70.9)
and spine factures (OR 0.54, 95% CI 0.370.87) compared with placebo. The risk reduction was
significant in women with eGFR 45 ml/min for both clinical and spine fractures, but NS in
women with eGFR <45 ml/min. (Level 1+)
Women with a reduced eGFR <45 ml/min had an increased risk of any clinical fracture (OR 1.3,
95% CI 1.01.6) and of spine fractures (OR 2.5, 95% CI 1.63.9) compared with women with
an eGFR 45 ml/min.334 (Level 1+)
Adverse events
There was no difference for adverse events among women with reduced renal function compared
with women without reduced renal function (p=0.189).334 (Level 1+)
Table 13.2 Summary of the safety and efficacy of bisphosphonates in preventing osteoporosis in people
with CKD (95% confidence intervals)
Reference
Population
332
People with
glomerulonephritis
+ high-dose
corticosteroid
Treatment
groups
N=12
risedronate
Osteoporotic
women
GFR < 30 ml/min
N=301
risedronate
N=271
placebo
Osteoporotic
women GFR
3050 ml/min
N=2034
risedronate
N=2037
placebo
Osteoporotic
women GFR
5080 ml/min
Size effect
Change in BMD
Fractures
Adverse events
RR 0.96 (0.911.02) NS
RR 0.93 (0.671.30) NS
RR 0.80 (0.312.04) NS
RR 1.02 (0.991.04) NS
RR 1.00 (0.881.14) NS
RR 0.88 (0.531.45) NS
RR 1.01 (0.991.02) NS
RR 0.63 (0.371.07) NS
RR 0.96 (0.851.09) NS
N=15
alfacalcidol
N=11
risedronate +
alfacalcidol
333
Outcomes
N=2161
risedronate
N=2192
placebo
continued
158
Table 13.2 Summary of the safety and efficacy of bisphosphonates in preventing osteoporosis in people
with CKD (95% confidence intervals) continued
Reference
Population
Osteoporotic
women
GFR <30 ml/min
Treatment
groups
N=301
risedronate
Outcomes
Size effect
Change in BMD
Change in BMD
Change in BMD
N=271
placebo
Osteoporotic
women
GFR 3050 ml/min
N=2034
risedronate
N=2037
placebo
Osteoporotic
women
GFR 5080 ml/min
N=2161
risedronate
N=2192
placebo
334
Osteoporotic
women
GFR <30 ml/min
N=232
Osteoporotic
women
GFR 3050 ml/min
N=2426
Osteoporotic
women
GFR 5080 ml/min
N=3086
Postmenopausal
Alendronate
women GFR
N=not stated
<45 ml/min (N=581)
Placebo
N=not stated
+ 5.6% (4.86.5)
+ 5.0% (4.05.9)
+ 6.7% (5.77.8)
Postmenopausal
Alendronate
women GFR
N= not stated
45 ml/min (N=5877)
Placebo
N=not stated
+ 4.8% (4.65.0)
+ 4.5% (4.24.8)
+ 6.6% (6.36.9)
Postmenopausal
Alendronate
women GFR
N=not stated
<45 ml/min (N=581)
Placebo
N=not stated
Clinical fractures
OR 0.78 (0.511.2) NS
Spine fractures
OR 0.72 (0.311.7) NS
Postmenopausal
Alendronate
women GFR
N= not stated
45 ml/min (N=5877)
Placebo
N=not stated
Clinical fractures
OR 0.81 (0.700.94)
Spine fractures
OR 0.50 (0.320.76)
continued
159
Table 13.2 Summary of the safety and efficacy of bisphosphonates in preventing osteoporosis in people
with CKD (95% confidence intervals) continued
Reference
Population
Treatment
groups
Outcomes
Size effect
GI adverse events
4.5%
2.2%
2.6%
Death
1.6%
2.1%
Alendronate
N= not stated
GI adverse events
Placebo
N=not stated
2.2% NS
3.2% NS
Death
1.9% NS
2.3% NS
Postmenopausal
Alendronate
women GFR
N= not stated
<45 ml/min (N=581)
Placebo
N=not stated
Postmenopausal
women GFR
45 ml/min
(N=5877)
13.2.6 RECOMMENDATIONS
R66
Offer bisphosphonates if indicated for the prevention and treatment of osteoporosis in people
with stage 1, 2, 3A or 3B CKD.
160
in the kidney to 1,25-dihydroxyvitamin D (calcitriol), which is the most active form. Vitamin D
deficiency can therefore occur as a result of decreased intake or absorption, reduced sun exposure,
increased hepatic catabolism, or decreased endogenous synthesis (via 25-hydroxylation in the liver
and subsequent 1-hydroxylation in the kidney). Active vitamin D has a variety of actions on
calcium, phosphate, and bone metabolism. By increasing intestinal calcium and phosphate
reabsorption and increasing the effect of parathyroid hormone (PTH) on bone, in health vitamin
D has the net effect of increasing the serum calcium and phosphate concentrations. Vitamin D
deficiency or resistance interferes with these processes, sometimes causing hypocalcaemia and
hypophosphataemia. Since hypocalcaemia stimulates the release of PTH, however, the
development of hypocalcaemia is often masked. The secondary hyperparathyroidism, via its
actions on bone and the kidney, partially corrects the hypocalcaemia but enhances urinary
phosphate excretion, thereby contributing to the development of hypophosphataemia. In people
with CKD the kidney component of this loop is increasingly compromised as CKD advances.
As renal function declines, the hydroxylating activity of renal 1-hydroxylase on 25-hydroxyvitamin D3 also decreases, resulting in decreased production of active vitamin D (1,25-dihydroxyvitamin D3) and decreased intestinal absorption of calcium. The decrease in calcium and active
vitamin D3 alleviates the repression of parathyroid hormone (PTH) production, resulting in
hyperproliferation of parathyroid cells. High PTH levels cause an increase in bone remodelling,
leading to high bone-turnover (osteitis fibrosa), loss of bone density and structure. This excess
bone remodelling liberates calcium and phosphorus from bone, resulting in hypercalcaemia and
hyperphosphataemia and increasing the risk for vascular calcification.
Vitamin D supplementation in people with CKD should therefore be driven by the underlying
metabolic abnormality. This in turn will depend on the stage of CKD but is complicated by the
fact that in the population with the highest prevalence of CKD, the older population, vitamin
D deficiency is common. Cutaneous vitamin D production and vitamin D stores decline with
age coupled with the fact that intake is often low in older subjects. Furthermore, even in those
with adequate vitamin D intake, achlorhydria, which is common in older people, limits vitamin
D absorption. Nutritional forms of vitamin D include ergocalciferol and cholecalciferol; active
forms of vitamin D include alfacalcidol, calcitriol and paricalcitol. Elderly patients are likely to
be vitamin D deficient from diet, lack of sunlight and poor absorption for which they will need
nutritional vitamin D. However as CKD progresses (particularly in stages 4 and 5), renal
function is impaired to such a degree that active vitamin D may also be required.
What type of vitamin D supplementation, if any, should be used in adults with CKD?
13.3.2 Methodology
Eight RCTs and one case series investigated the safety and efficacy of various natural and
synthetic vitamin D metabolites to treat secondary hyperparathyroidism and to prevent bone
loss in people with pre-dialysis CKD. Outcomes of interest included adverse events, fractures,
changes in serum calcium, phosphorus, PTH, osteocalcin, alkaline phosphatase, GFR, and bone
mineral density. All of these studies are limited by small sample sizes (N=25220), and very few
presented intention to treat analyses. There were no studies of acceptable methodological
quality that compared different vitamin D metabolites head-to-head.
161
Four RCTs335338 compared calcitriol supplementation to placebo in people with CKD. Two of
these RCTs titrated the dose of calcitriol from 0.25 g/day up to 0.5 g/day.335,336 In the RCT of
Przedlacki et al., treatment with calcitriol (0.25 g/day, N=13, 12 months follow-up) was
compared with placebo (N=12) in people with eGFR <51.2 ml/min. In the RCT of Ritz et al., a
low dose of calcitriol (0.125 g/day, N=28, follow-up 1 year) was compared with placebo (N=24)
in people with nondiabetic CKD and abnormal iPTH levels (iPTH >6 pmol/l on 3 separate
occasions). The Baker et al. study (N=13, follow-up 12 months) was excluded due to small sample
size, high dropout rate, and lack of baseline data comparison between the two trial arms.
One RCT compared 6 months of treatment with calcitrol (N=8, 1 g/day) or calcidiol (N=9,
4000 IU/day) in people with chronic renal failure.339 This study was rejected because there was
no indication of blinding, concealment, intention to treat, and statistical power to detect
differences between the two groups.
Two RCTs investigated the effects of treatment with alfacalcidol (1--hydroxycholecalciferol)
compared to placebo in people with mild to moderate CKD (creatinine clearance
1060 ml/min).340,341 The Hamdy et al. RCT (N=89 alfacalcidol and N=87 placebo, 24 months
follow-up) titrated the dose of alfacalcidol from 0.25 to 1 g/day. Most of the participants had
abnormal bone histology at baseline (NS difference between the trial arms). The smaller RCT
of Rix et al. (N=36, 18 months follow-up) titrated alfacalcidol from 0.25 to 0.75 g/day.
A pooled analysis of 3 RCTs with identical inclusion/exclusion criteria and different dosing
regimens (3 times weekly or once daily) compared paricalcitol (N=107, 6 months follow-up,
mean dose was 1.3 to 1.4 g/day) with placebo (N=113) in people with CKD and hyperparathyroidism (iPTH 150 pg/ml). Although this study was not a systematic review, it was
included as an RCT (albeit pooled) due to lack of studies of non-dialysis CKD populations.342
One retrospective case series examined changes in serum calcium, phosphate, iPTH, and
adverse events before and after 6 months treatment with ergocalciferol (vitamin D2 ) in men
with stage 3 CKD and plasma iPTH >70 ng/l (N=44) or stage 4 CKD and plasma iPTH
>110 ng/l (N=22).343
Serum calcium
One RCT showed that serum calcium significantly increased with calcitrol (0.25 titrated to
0.5 g/day) compared with placebo.336 (Level 1+)
Two RCTs showed NS changes in mean serum calcium in people taking calcitrol (0.25 g/day
steady or 0.125 g/day) or placebo.337,338 (Level 1 +)
162
Serum phosphorus
Three RCTs showed that mean serum phosphate did NS change in either the placebo or calcitrol
groups.336-338 (Level 1 +)
Serum osteocalcin
One RCT showed that mean serum osteocalcin significantly decreased in the calcitrol group,
whereas osteocalcin significantly increased in the placebo group.337 (Level 1 +)
163
Adverse events
Hypercalcaemia (>2.6 mmol/l) was observed in 2/13 people receiving calcitrol and 0/12 receiving
placebo. Hyperionised calcaemia (blood ionised Ca >1.29 mmol/l) occurred in 5/13 on calcitrol
and 3/12 in the placebo group.337
There was no hypercalcaemia (>2.7 mmol/l on three consecutive occasions) in either calcitrol
(0.125 g/day) or placebo groups.338
There was no hyperphosphataemia (>2.2 mmol/l on 3 consecutive occasions) in either calcitrol
(0.125 g/day) or placebo groups.338
Hyperphosphataemia (P >1.5 mmol/l) occurred in 3/12 placebo and 10/13 randomised to
calcitrol (NS between groups).337 (Level 1+)
Table 13.3 Summary of studies comparing calcitrol with placebo
Duration
(months)
Study
Population
336
Calcitriol
(N)
Placebo
(N)
14
14
Outcome
Size effect
Change iPTH
(g/l)
337
12
13
12
338
12
28
24
Change iPTH
(pmol/l)
337
12
13
12
336
14
14
Change Serum
alkaline
phosphatase (U/I)
continued
164
Study
Population
Duration
(months)
Calcitriol
(N)
Placebo
(N)
337
12
13
12
Outcome
Size effect
Change Serum
alkaline
phosphatase (U/I)
336
15
15
Change in CrCl
Calcitriol: 5ml/min
(approx.), p<0.01
Placebo: 5ml/min (approx.),
p<0.01
NS between groups
337
12
13
12
Change in GFR
337
12
13
12
Change Bone
Mineral Density
(g/cm2)
continued
165
Study
Population
Duration
(months)
Calcitriol
(N)
Placebo
(N)
336
14
14
Outcome
Size effect
Change Bone
volume
NS change placebo or
calcitriol.
Change Osteoid
volume
Change Osteoid
thickness (m)
Change Osteoid
surface
Change Eroded
surface
Change Osteoclast
surface
Change Bone
formation rate
Change Mineral
apposition rate
(m/day)
Serum calcium
Two RCTs showed that mean serum calcium increased significantly in people taking
alfacalcidol, while there were NS changes in calcium in people taking placebo, p<0.001 between
groups.340,341 (Level 1 +)
166
Serum phosphorus
Two RCTs showed that there were NS changes in serum P in the alfacalcidol or placebo
groups.340,341 (Level 1+)
Serum osteocalcin
Osteocalcin significantly decreased in the alfacalcidol group, whereas there was NS change in
osteocalcin in the placebo group. At the end of the study only 1 person in the alfacalcidol group
had osteocalcin levels above the reference range (4.231.4 ng/ml), whereas 6 people in the
placebo group had osteocalcin levels exceeding reference ranges.341 (Level 1+)
The proportion of people with bone abnormalities at the beginning of the study was similar
between the placebo (73%) and alfacalcidol (76%) groups. After 24 months treatment, 54% of
people taking alfacalcidol and 82% on placebo had bone abnormalities (no p given). (Level 1+)
Fibrosis significantly decreased in people taking alfacalcidol, while fibrosis increased in the
placebo group, p=0.0002 between groups. (Level 1+)
Osteoid volume, osteoid surface, osteoblast surface, and osteoclast surface all decreased
significantly in the alfacalcidol group, whereas there were NS changes in any of these parameters
in the placebo group, p<0.05 between groups for each outcome. (Level 1+)
There were NS differences in mineral apposition rate between placebo or alfacalcidol groups.
(Level 1+)
Bone formation rate decreased significantly in alfacalcidol group, but there was NS change in
placebo and NS difference between groups. (Level 1+)
Bone resorption decreased in people taking alfacalcidol compared with placebo. The eroded
bone surface significantly decreased in the alfacalcidol group while it increased in the placebo
group, p=0.04 between groups. Also, alfacalcidol was associated with a significant decrease of
active eroded surface compared with placebo, p=0.0006 between groups.340 (Level 1+)
Adverse events
Mild hypercalcaemia (>2.63 mmol/l on 2 occasions) was seen in 10/89 patients receiving
alfacalcidol and 3/87 patients receiving placebo (p=0.09, NS). Severe hypercalcaemia
(>3.00 mmol/l on 1 occasion) was observed in 4 people taking alfacalcidol and 0 people on
placebo.340 (Level 1+)
Hypercalcaemia occurred in 1/18 people on alfacalidol.341 (Level 1+)
Mild GI disturbances were reported in 6/89 people on alfacalcidol and 1/87 on placebo.340
(Level 1+)
Pseudogout was reported by 2/89 people on alfacalcidol.340,340 (Level 1+)
Table 13.4 Summary of studies comparing alfacalcidol with placebo
Study
Population
340
Duration
(months)
Alfacalcidol
(N)
Placebo
(N)
24
89
87
Outcome
Size effect
Change iPTH
(pmol/l)
Alfacalcidol:
1.6 pmol/l, NS
Placebo +7.3 pmol/l,
p<0.001
341
18
16
15
Alfacalcidol:
47%, p<0.05
Placebo NS
p<0.05 between groups
continued
168
Study
Population
341
Duration
(months)
Alfacalcidol
(N)
Placebo
(N)
18
16
15
Outcome
Size effect
Change osteocalcin
(%)
Alfacalcidol:
24%, p<0.05
Placebo: +25%, NS
p<0.05 between groups
341
18
16
15
Alfacalcidol:
48% p<0.05
Placebo: NS
340
24
89
87
Change in CrCl
Alfacalcidol:
5.7ml/min
Placebo: 4.0 ml/min
NS between treatments
341
18
16
15
Change in CrCl
Decreased significantly in
both placebo and
alfacalcidol groups
NS between treatments.
341
18
16
15
Change Bone
Mineral Density
continued
169
Study
Population
340
Duration
(months)
Alfacalcidol
(N)
Placebo
(N)
24
55
45
Outcome
Size effect
Change Bone
volume
Alfacalcidol: 1.22
Placebo: 1.09
p=0.75 between groups
24
55
45
Change Osteoid
volume
24
55
45
Change Osteoid
surface
24
55
45
Change Eroded
surface
Alfacalcidol: 3.76
Placebo: +0.45
p=0.04 between groups
24
55
45
Change Osteoclast
surface
Alfacalcidol: 0.30, NS
NS placebo: +0.17
p=0.002 between groups
24
55
45
Change Bone
formation rate
24
55
45
Change Mineral
apposition rate
(m/day)
NS changes in alfacalcidol
or placebo and NS between
groups (p=0.34)
Serum calcium
Mean serum calcium increased slightly in people taking paricalcitol, while there were small
decreases in serum calcium in the placebo group, NS between groups.342 (Level 1+)
Serum phosphorus
There were NS changes in serum phosphate in the paricalcitol or placebo groups.342 (Level 1 +)
Serum osteocalcin
Serum osteocalcin significantly decreased in the paricalcitol group, compared with an increase
in osteocalcin in the placebo group (p<0.001 between groups).342 (Level 1+)
Change in GFR
After 6 months, eGFR decreased in both placebo and paricalcitol groups, but there were NS
differences between treatments.342 (Level 1+)
Urinary deoxypryidinoline
There were NS differences between paricalcitol or placebo groups for changes in urinary
deoxypryidinoline.342 (Level 1+)
Urinary pyridinoline
Urinary pyridinoline decreased significantly in the paricalcitol group, compared with an
increase in the placebo group (p=0.006 between groups).342 (Level 1+)
Adverse events
Hypercalcaemia (2 consecutive Ca >2.62 mmol/l) occurred in 2 people on paricalcitol and no
people on placebo (NS).
Hyperphosphataemia (2 consecutive PO4 >1.78 mmol/l) occurred in 11 people on paricalcitol
and 13 people on placebo (NS).342 (Level 1+)
171
Study
Population
342
3 pooled RCTs:
CKD, iPTH 150 pg/ml,
Ca 1.992.40 mmol/l
and PO4 1.68 mmol/l.
Duration
(months)
Paricalcitol
(N)
Placebo
(N)
Outcome
Size effect
101
108
101
108
2 consecutive
decreases 30%
of iPTH
Paricalcitol: 91%
Placebo: 13%
p<0.001 between groups
100
104
101
107
82
93
Change in GFR:
Serum phosphate
Mean serum phosphate did NS change after 6 months treatment with ergocalciferol in the
whole group, stage 3 CKD alone or stage 4 CKD alone.343 (Level 3)
Adverse events
There were no cases of hypercalcaemia or hyperphosphataemia before or after ergocalciferol.343
(Level 3)
172
13.3.6 RECOMMENDATIONS
R67
R68
Detailed advice concerning management of bone and mineral disorders in CKD is beyond the scope of this
guideline. Where uncertainty exists seek advice from your local renal service.
173
Median Hb in men
(g/dl)
Median Hb in women
(g/dl)
Prevalence of
anaemia*
60
14.9
13.5
1%
30
13.8
12.2
9%
15
12.0
10.3
33%
NICE clinical guideline 39 (Anaemia management in people with CKD)27 recommended that
management of anaemia should be considered in people with anaemia of CKD when their
haemoglobin (Hb) level is less than or equal to 11 g/dl. The guideline was written for people
with a GFR <60 ml/min/1.73 m2 already known to have a haemoglobin level 11 g/dl but gave
no recommendations about testing for anaemia.
In the UK we know that from primary care data, 85% of patients who have had a serum creatinine
measurement have also had their haemoglobin level measured.19 This study demonstrated that
the prevalence of anaemia rises sharply from CKD stage 3B onwards (Table 14.2), suggesting the
importance of testing for anaemia at levels of GFR <45 ml/min/1.73 m2.
Table 14.2 Anaemia identification in CKD: prevalence of Hb <11 g/dl in the general population
GFR stratum
<30 ml/min/
1.73 m2
3044 ml/min/
1.73 m2
4559 ml/min/
1.73 m2
60 ml/min/
1.73 m2
Hb tested, N (%)
439 (83.6)
2057 (83.1)
7308 (83.7)
22581 (85.1)
44 (10)
84 (4.1)
213 (2.9)
611(2.7)
Adapted and reproduced by permission from Macmillan Publishers Ltd: Kidney International (Stevens PE, ODonoghue DJ,
de Lusignan S et al. Chronic kidney disease management in the United Kingdom: NEOERICA project results. Kidney
International 2007; 72(1):9299).19 Copyright 2007.
175
14.1.2 RECOMMENDATION
R69
176
If not already measured, check the haemoglobin level in people with stage 3B, 4 and 5 CKD to
identify anaemia (Hb <11.0 g/dl see NICE clinical guideline 39: Anaemia management in
people with chronic kidney disease). Determine the subsequent frequency of testing by the
measured value and the clinical circumstances.
15 Information needs
15.1 Information, education and support for people with CKD
and their carers
15.1.1 Clinical introduction
People accessing NHS services need to be provided with education to allow them to understand
their condition and treatment and to be involved in decisions about their care. Current NHS
policy recognises the need to develop patient-led services345 and that education is of benefit to
those with long term conditions, giving them skills and knowledge and ensuring they can be
actively involved in planning their own care.346
This idea has been actively promoted within renal services, with the Renal National Service
Framework Standard 1 stating that people with CKD should have access to information that
enables them and their carers to make informed decisions and encourages partnership in
decision-making.347
This policy reflects the desire of people with CKD themselves to have information and
education. A study by Ormandy et al.348 concluded that people with CKD have identifiable
information needs which change at different times as their condition progresses.
Information has typically been provided in the form of verbal information received face to face
from health professionals in a clinical setting, or by way of written information such as leaflets
provided at clinical appointments. Other ways of providing information include audio-visual
methods such as CDs, videos and DVDs. Coulter et al.349 have identified that where
information leaflets are to be used in support of patients involvement in treatment decisions,
they must contain relevant, research-based data in a form that is acceptable and useful to
patients. In addition, such information should be based on the needs of those who will use the
information and they should be involved in developing and testing the information.
However, although information is necessary to achieve informed decision-making, it is not
always sufficient on its own, even where it is of good quality. Studies show that the context in
which the information is given and providing support for the decision-making process are also
important.350 Therefore education programmes are being developed to ensure that people with
CKD can not only access appropriate information but learn how to use it to make decisions
about their own care.
What information, education, and support are needed for CKD patients and their carers to
understand and cope with the diagnosis, treatment and outcome of CKD?
15.1.2 Methodology
There were no studies that examined the impact of education, information, or support on
people with early (stage 13) CKD. There were no studies that investigated support systems for
carers of people with CKD. Most educational intervention studies were conducted in people
177
with advanced stage CKD prior to initiation of dialysis. The outcomes of interest were quality
of life, compliance with medication, and preparation for ESRD therapy (timely creation for
access for dialysis, hepatitis vaccinations, emotional issues surrounding initiation of dialysis,
and choice of dialysis modality).
One open label RCT assessed the intent to start home-care dialysis in people with eGFR
<30 ml/min/1.73 m2 randomised to standard education (N=35, education on kidney disease,
dietary instruction, and different dialysis modalities) or to a 2 phase education + standard care
intervention (N=35, booklets and videos discussing advantages/disadvantages of self-care dialysis,
followed by a group discussion of self-care dialysis with a nephrologist and predialysis nurse).351
One retrospective Japanese cohort study assessed planned initiation of renal replacement
therapy (RRT) and choice of dialysis modality in people initiating dialysis who had received
predialysis education (N=70: lectures on chronic renal failure, treatment, daily-life instructions,
explanations of different dialysis modalities and dietary therapy) compared with people who
did not receive predialysis education (N=106: standard dialysis information was provided by
the attending physician if requested by the patient).352
An American retrospective cohort study assessed timing of vascular access in people exposed to
the Healthy Start Clinic education program (N=61: consisting of lectures, handbooks, and slide
presentations on chronic renal failure, treatment, explanations of dialysis modalities and
dietary therapy) compared with patients who did not receive the Healthy Start Clinic education
program (N=86: conventional care with dialysis modality information, CKD video, meeting
with a social worker in hospital).353
A Canadian cohort study examined dialysis modality choice and urgent dialysis initiation in
people taking a predialysis clinic education program (N=37), compared with people receiving
standard care (N=39). The clinic education program consisted of discussions with a nurse
educator, physician, social worker, and nutritionist about renal function, blood pressure, bone
disease, and diet therapy over multiple visits.354
A potential source of bias in all the cohort studies may be the voluntary participation in the
education group, such that these participants may have already been more concerned about
their health, acted to enhance their health, and thus be better prepared for dialysis initiation
compared with participants who did not receive education.
The effect of predialysis education in adults with CKD is summarised in Table 15.1 at the end
of the evidence statements.
178
15 Information needs
Population
Intervention
Comparison
Outcome
Size effect
352
People initiating
dialysis
Educational
intervention
N=70
No educational
intervention
N=106
Planned initiation
of dialysis
Education: 65%
No education: 35%
p=0.001
354
People initiating
dialysis
Clinic-based
education
N=37
Standard care
N=39
Urgent dialysis
start
351
Standard care
+ 2 phase
educational
intervention
N=28
Standard care
N=34
Intent to start
home-care dialysis
Education + standard
care: 82.1%
Standard care: 50%
p=0.015
continued
179
Population
Intervention
Comparison
Outcome
Size effect
352
People initiating
dialysis
Educational
intervention
N=70
No educational
intervention
N=106
Choice of
haemodialysis
Education: 90%
No education: 95% NS
Choice of
peritoneal dialysis
Education: 10%
No education: 5% in NS
354
People initiating
dialysis
Clinic-based
education
N=37
Standard care
N=39
Choice of
peritoneal dialysis
Education: 53%
Standard care: 42%
NS
353
Healthy Start
program
educational
intervention
N=61
No Healthy Start
educational
intervention N=86
Permanent
Vascular Access
before Initiation of
Dialysis
HS education: 77%,
No HS education: 36%
p<0.001
Arteriovenous
fistulas placed
before dialysis
initiation
HS education: 74%,
No HS education: 38%
p<0.05
Permanent
Vascular Access
used for Initiation
of Dialysis
HS education: 49%
No HS education: 23%
p<0.01
Arteriovenous
fistulas used to
initiate dialysis
HS education: 70%,
No HS education: 30%
p<0.01
Grafts used to
initiate dialysis
HS education: 30%,
No HS education: 70%
p<0.01
352
People initiating
dialysis
Educational
intervention
N=70
No educational
intervention
N=106
Education: 5%
No education: 25%,
p<0.0003
353
Healthy Start
Program
educational
intervention
N=61
No Healthy Start
educational
intervention N=86
Use of a
temporary catheter
to initiate dialysis
HS Education: 51%
No HS education: 77%
p<0.001
15 Information needs
agreed that it was important that people were given information about their prognosis and that
they should be aware of options for dialysis access prior to having to make a decision about this.
The GDG agreed that it was not sufficient for people simply to be given information about
CKD and its treatment. This information had to form part of a programme that educated them
about the disease. It was agreed that it was important that after the education programme,
peoples understanding should be assessed. It was also agreed that programmes should be run
by clinicians who have sufficient knowledge to be able to answer peoples questions.
Older people do not always learn easily from information given on paper and some people may
need psychological support to help them cope with the consequences of the information that
they have been given.
A summary of research findings by Ormandy et al.348 identified key information needs of
people in renal units in the UK. The GDG used these to guide making recommendations.
We have not found evidence of cost-effectiveness. We do not believe this recommendation will
have a big cost impact for the NHS since this is part of the existing National Service Framework
and such programmes are already widespread.
15.1.6 RECOMMENDATIONS
R70
Offer people with CKD education and information tailored to the stage and cause of CKD,
the associated complications and the risk of progression.
R71
When developing information or education programmes, involve people with CKD in their
development from the outset. The following topics are suggested:
G
What is CKD and how does it affect people?
G
What questions should people ask about their kidneys when they attend clinic?
G
What treatments are available for CKD, what are their advantages and disadvantages and
what complications or side effects may occur as a result of treatment/medication?
G
What can people do to manage and influence their own condition?
G
In what ways could CKD and its treatment affect peoples daily life, social activities, work
opportunities and financial situation, including benefits and allowances available?
G
How can people cope with and adjust to CKD and what sources of psychological support
are available.
G
When appropriate, offer information about renal replacement therapy (such as the
frequency and length of time of dialysis treatment sessions or exchanges and pre-emptive
transplantation), and the preparation required (such as having a fistula or peritoneal
catheter).
G
Conservative management may be considered where appropriate.
R72
Offer people with CKD high quality information or education programmes at appropriate
stages of their condition to allow time for them to fully understand and make informed
choices about their treatment
R73
R74
Healthcare professionals working with people with CKD should take account of the
psychological aspects of coping with the condition and offer access to appropriate support
(for example, support groups, counselling or a specialist nurse).
181
15.2.2 Methodology
The literature was reviewed to assess the utility of computerised tools (decision support systems
and information technologies) to aid primary care workers in identifying people with CKD and
in offering the most appropriate and timely treatments. Outcomes of interest were appropriate
investigations and follow-up, referral, medicines management, and achieving clinical targets.
The New Opportunities for Early Renal Intervention by Computerised Assessment
(NEOERICA) project used computer searching to extract a retrospective dataset of all patients
with a valid serum creatinine measurement from 17 primary care practices in the UK
(N=38,262 with valid serum creatinine measures).19 The aim of this study was to ascertain if
computerised medical records contain sufficient information to estimate the prevalence of
CKD, its comorbidities, as well as medication usage and BP targets achieved. Manual searching
182
15 Information needs
of medical records from 1 practice (N=492 with stages 35 CKD identified by computer
searching) was used to test the validity of computer searching to estimate the prevalence of
CKD.355 In both of these retrospective observational studies, ethnicity was unreliably reported,
and the CKD prevalence estimation was limited to only stages 3 to 5 due to poor recording of
proteinuria and haematuria in the medical records. Serum creatinine measurements were
calibrated to the original MDRD study in Stevens et al., but not in Anandarajah et al.
Two publications from the Optimal Renal Care UK (ORC UK) study assessed the utility of a
disease management programme (DMP) that was guideline- and algorithm-based to identify,
manage, and appropriately refer people with CKD.356,357
In a case series study, a clinical tool to identify people at risk of rapid progression of kidney
disease (25% decline in mean eGFR over 2 years) was developed in adults 66 years (mean age
76.1 years, N=6789) and validated in a second cohort of older adults (N=3395). Medications
dispensed prior to the index creatinine measurements were used to determine disease
categories, which were considered in a stepwise logistic regression analysis. Risk scores were
calculated for each subject and then categorised into risk classes (I to V).358 Albuminuria was
not included in the model and disease categories assigned based on medication may misclassify
and underestimate true prevalence of a certain disease.
Another study investigated the ability of the Framingham prediction equation to predict 5 year
and 10 year risk of cardiac events (myocardial infarction and fatal coronary heart disease) in
people with CKD from the pooled ARIC and CHS studies (N=934).359
183
<130/80 mmHg. Only 571/6235 (9.2%) people with hypertension and eGFR 4559 ml/min/
1.73 m2 achieved BP <130/80 mmHg. Only 270/1313 (20%) of people with diabetes, hypertension,
and eGFR <60 ml/min/1.73 m2 achieved target BP <130/80 mmHg.19 (Level 3)
Risk tool for predicting rapid progression of kidney dysfunction (25% decline in
mean eGFR between the two study periods)
Multivariate analysis showed that age >75 years old, cardiac disease, diabetes, gout, and antiemetic drug use were significantly associated with rapid progression of kidney dysfunction. In
both the derivation (N=6789) and validation cohorts (N=3395), people in the Class V risk
index had triple the risk of rapid renal disease progression compared with people in the Class I
risk index. The c-statistic for the model was 0.59, indicating a modest ability to discriminate
between people with and without risk of rapid renal disease progression.358 (Level 3)
Utility of the Framingham equation to predict cardiac events in people with CKD
The Framingham prediction equation had poor discrimination (the ability to separate those
who had cardiac events from those who did not) in the CKD cohort. The Framingham equation
correctly identified men with CKD who would develop a cardiac event within 10 years only
184
15 Information needs
60% of the time, compared with 69% of the time in the non-CKD male cohort and 73% in the
original Framingham cohort. In women with CKD, discrimination was 73% for 10-year cardiac
events compared with 76% in the original Framingham cohort.359 (Level 3)
The Framingham equation under-predicted cardiac events when men with CKD were stratified
into quintiles of Framingham Risk. The 5-year calibration for men was poor (chi-square 33.4,
p<0.001) and the 10-year calibration was also poor (chi-square 71.3, p<0.001). The Framingham
equation under-predicted cardiac events in women with CKD and had poor 5- and 10-year
calibration. Recalibrated models performed better, although prediction remained poor in men
with CKD. In women with CKD, re-calibration showed NS difference in predicted and observed
cardiac events in 5- and 10-year probability models.359 (Level 3)
15.2.6 RECOMMENDATIONS
There are no recommendations.
185
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204
Question ID
Question wording
TEST 1
Systematic reviews,
RCTs, cohort studies,
diagnostic studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
TEST 4
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
TEST 3
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
TEST 2
Systematic reviews,
RCTs, observational
studies, diagnostic
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
ULTRA 1
Medline 19662008
Cochrane 18002008
US Guidelines
Clearinghouse (2007)
National Electronic
Library for Health (2007)
National Institute of
Health and Clinical
Excellence Website
(2007)
Health Technology
Assessment Website
(2007)
OUTS 1
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
IDEN 1
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
PROG 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
continued
Study type
filters used
Question ID
Question wording
RISK 2
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
REFER 1
Medline 19662008
Cochrane 18002008
US Guidelines
Clearinghouse (2007)
National Electronic
Library for Health (2007)
National Institute of
Health and Clinical
Excellence Website
(2007)
Health Technology
Assessment Website
(2007)
LIFE 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
DIET 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
BP 1
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
HYPR 1
Systematic reviews,
RCTs
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
MONIT 1
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
RISK 1
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
HYPR 2
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
continued
Study type
filters used
Question ID
Question wording
STAT 1
Systematic reviews,
RCTs
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
LIPID 1
Systematic reviews,
RCTs
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
ANTI 1
Systematic reviews,
RCTs
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
URIC 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
HAEM 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
BONE 1
Systematic reviews,
RCTs, observational
studies
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
BONE 2
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
BONE 3
Systematic reviews,
RCTs
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
EDUC 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
TOOLS 1
Medline 19662008
Embase 19802008
Cochrane 18002008
Cinahl 19822008
NOTE: The final cut-off date for all searches was 8 February 2008.
Guideline title
Chronic Kidney Disease: Early identification and management of chronic kidney disease in
adults in primary and secondary care.
1.1
Short title
Chronic Kidney Disease.
Background
a) The National Institute for Health and Clinical Excellence (NICE or the Institute) has
commissioned the National Collaborating Centre for Chronic Conditions to develop a
clinical guideline on chronic kidney disease for use in the NHS in England and Wales.
This follows referral of the topic by the Department of Health. The guideline will provide
recommendations for good practice that are based on the best available evidence of
clinical and cost effectiveness.
b) The Institutes clinical guidelines will support the implementation of National Service
Frameworks (NSFs) in those aspects of care where a Framework has been published. The
statements in each NSF reflect the evidence that was used at the time the Framework was
prepared. The clinical guidelines and technology appraisals published by the Institute
after an NSF has been issued will have the effect of updating the Framework. The NSF for
Renal Services (2005) is of particular relevance to this guideline.
c) NICE clinical guidelines support the role of healthcare professionals in providing care in
partnership with patients, taking account of their individual needs and preferences, and
ensuring that patients (and their carers and families, where appropriate) can make
informed decisions about their care and treatment.
b)
c)
d)
e)
The guideline
a) The guideline development process is described in detail in two publications which are
available from the NICE website (see Further information). The guideline development
process: an overview for stakeholders, the public and the NHS describes how organisations
can become involved in the development of a guideline. Guideline development methods:
information for National Collaborating Centres and guideline developers provides advice on
the technical aspects of guideline development.
b) This document is the scope. It defines exactly what this guideline will (and will not)
examine, and what the guideline developers will consider. The scope is based on the
referral from the Department of Health (see Appendix).
c) The areas that will be addressed by the guideline are described in the following sections.
4.1
Population
4.1.1
4.1.2
4.2
Healthcare setting
Primary and secondary NHS healthcare, including referral to tertiary care.
4.3
Clinical management
The guideline will cover:
a) Early detection/identification of people with chronic kidney disease (including diagnostic
tests).
b) Management of chronic kidney disease. For example this will include management of:
G
Hypertension and lipids, specific to CKD
G
Proteinuria/albuminuria
G
Progressive kidney disease
G
Renal bone disease
G
Acidosis
G
Hyperuricaemia
And will incorporate
G
The utility of specific pharmacological interventions
G
Non-pharmacological interventions (such as dietary intervention, smoking cessation
and exercise)
4.4
Status
4.4.1
Scope
This is the consultation draft of the scope. The consultation period is 30th August to
27th September 2006.
The guideline will cross refer where appropriate to the following NICE guidance.
G
Cinacelcet hydrochloride for the treatment of secondary hyperparathyroidism in patients
with end stage renal disease on maintenance dialysis therapy NICE technology appraisal.
Expected date of publication January 2007.
G
Type 1 diabetes: diagnosis and management of type 1 diabetes in children, young people
and adults. NICE clinical guideline no.15 (2004). Available from
http://www.nice.org.uk/CG015
G
Hypertension: the management of hypertension in adults in primary and secondary care.
NICE clinical guideline no. 34 (2006). Available from http://www.nice.org.uk/CG034
G
Anaemia management in people with chronic kidney disease (CKD). NICE clinical
guideline. Expected date of publication September 2006.
G
Type 2 diabetes: the management of type 2 diabetes (update). NICE clinical guideline.
Expected date of publication February 2008.
G
Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in
individuals at high risk. NICE clinical guideline. Publication date to be confirmed.
4.4.2
Development of recommendations
The development of the guideline recommendations will begin in October 2006.
Further information
Information on the guideline development process is provided in:
G
The guideline development process: an overview for stakeholders, the public and the
NHS
Guideline development methods: information for National Collaborating Centres and
guideline developers
These booklets are available as PDF files from the NICE website (http://www.nice.org.uk/
guidelinesprocess). Information on the progress of the guideline will also be available from the
website.
To evaluate which is the most cost-effective strategy to measure renal function in routine
clinical practice.
To determine which high-risk group for CKD should be tested.
C.2 Methods
C.2.1 Study population
The case for testing people with diabetes for CKD is already well established: NICE guidelines
recommend regular testing and economic evaluations have found testing to be costeffective.29,155157,183 Therefore we developed models for two other high-risk groups.
Model 1 Non-diabetic, hypertensive adults
Model 2 Non-diabetic, non-hypertensive adults (age 55)
The model was run for different age-sex groups. Other populations, such as people with a
family history of ESRD, were not explicitly considered, since their epidemiology is not as well
known as in people with hypertension and diabetes. However, a sensitivity analysis was
conducted to determine the cost-effectiveness of testing at different levels of prevalence.
C.2.2 Comparators
The GDG identified the following testing strategies:
1. No testing strategy
2. Reagent 1 strategy: GFR + Proteinuria Reagent strip test
G positive strip ACR
G negative strip No further testing
3. Reagent 2 strategy: GFR + Proteinuria Reagent strip test
G positive strip ACR
nd Reagent Strip test
G negative strip 2
nd strip ACR
G negative strip positive 2
nd strip No further testing
G negative strip negative 2
4. ACR strategy: GFR + ACR
In both models the no testing strategy involved natural progression of CKD. But under the
testing strategies, for true positives the progression is slowed and mortality reduced due to
treatment with ACE inhibitors or ARBs.
Direct comparison of PCR with ACR in terms of diagnostic sensitivity and specificity was not
possible since these two tests cannot meaningfully be compared against the same reference
standard. However, a sensitivity analysis was conducted to find the level of sensitivity of PCR
(relative to ACR) that would make PCR the more cost-effective strategy.
10
Two earlier models,156,157 have evaluated early identification of CKD but not from a UK
perspective (see sections 4.2.3 and 4.2.5 of the full guideline). These models have informed the
development of our model.
The model follows the NICE reference case,1 as follows. The costs were measured from the
perspective of the National Health Services (NHS) and Personal Social Services (PSS). Health
outcome was measured in terms of quality-adjusted-life-years (QALYs), where one QALY is
equal to one year of full health. An annual discount rate of 3.5% was used for both costs and
effects.
Proteinuria
eGFR >60 ml/min/1.73 m2
pGFRless60_HYP
+
M [ ]
pPUless60_HYP
No proteinuria
#
No testing
Proteinuria
eGFR >60 ml/min/1.73 m2
pPUmore60_HYP
No proteinuria
#
Figure C.1 Decision tree arm for the no testing strategy.
No testing
[+]
Proteinuria
pPUless60_HYP
Reagent strip
test 1
1
Reagent strip
test 1
1
GFR + 2 reagent
strips
Proteinuria
pPUmore60_HYP
Reagent strip
test 1
1
No proteinuria
#
GFR + 1 reagent
strip
GFR + ACR
Reagent strip
test 1
1
True positive
sens_strip
ACR
1
False negative
#
Reagent strip
test 2
1
True negative
spec_strip
Reagent strip
test 2
1
False positive
#
ACR
True positive
sens_strip
ACR
False negative
#
Reagent strip
test 2
1
True negative
spec_strip
Reagent strip
test 2
1
False positive
#
ACR
1
True positive
sens_acr M [+]
False negative
M [+]
#
True positive
sens_strip
ACR
1
True positive
sens_acr M [+]
False negative
M [+]
#
False negative
M [+]
#
True negative
spec_strip
False positive
#
ACR
1
True negative
spec_acr
False positive
#
True negative
spec_acr
False positive
#
True positive
sens_acr
False negative
#
True positive
spec_strip
ACR
1
False negative
#
True negative
spec_strip
False positive
#
ACR
1
True positive
sens_acr
False negative
#
True negative
spec_acr
False positive
#
True negative
spec_acr
False positive
#
[+]
[+]
11
No testing
[+]
GFR + 2 reagent
strips
[+]
High-risk population
hypertension
Proteinuria
pPUless60_HYP
Reagent strip
test 1
1
No proteinuria
#
Reagent strip
test 1
1
GFR + 1 reagent
strip
Proteinuria
pUmore60_HYP
Reagent strip
test 1
1
No proteinuria
#
Reagent strip
test 1
1
[+]
True positive
sens_strip
False positive
#
ACR
True positive
spec_strip
ACR
False positive
#
Test positive
_p63
True positive
M [+]
_p61
False positive
_p62
Test negative
_p66
False negative
M [+]
_p64
True negative
_p65
Test positive
_p75
True positive
_p73
False positive
_p74
ACR
1
GFR + ACR
ACR
1
Test negative
_p78
False negative
_p76
True negative
_p77
Moderate
CKD*
Stage 34
End
Stage 5
RRT
Death from
all causes
Figure C.5 Markov model for patients diagnosed with CKD and proteinuria.
12
False negative
#
True negative
spec_acr
[+]
High-risk population
hypertension
True positive
sens_acr M [+]
False negative
M [+]
#
False negative
M [+]
#
True negative
spec_strip
ACR
ACR
1
True negative
spec_acr
False positive
#
True positive
sens_acr
False negative
#
True negative
spec_acr
False positive
#
For the purposes of the model, the GFR estimation was assumed to be 100% sensitive and
specific. The 100% specificity is based on the assumption that false positives will be
eliminated because we recommend that a positive test is followed by a second eGFR.
In the base case analysis, the ACR was assumed to be 100% sensitive and specific. The
100% specificity is based on an assumption that false positives will be eliminated by a
second measurement to quantify albuminuria / proteinuria. Alternative values for the
sensitivity of ACR were tested by sensitivity analysis.
Health gain was based on the prescription of high dose ACE inhibitor/ARB therapy on
diagnosis of CKD. These drugs reduce mortality and slow down the progression of disease.
Health gain and long-term costs were estimated only for those patients who have both
CKD (eGFR <60) and proteinuria. This was a simplification made to speed up the
development of the model, but the model should still capture most of the costs and
health benefits as long as eGFR and ACR are relatively specific.
In the absence of diagnosis of CKD (unscreened, false negatives, and true negatives),
patients are not prescribed ACE inhibitor/ARB therapy. They receive no CKD treatment
until renal replacement therapy (in the discussion below, we consider the impact of
relaxing this assumption).
Cost effects
Testing strategies will increase spending in the short-term (including staff time, test
costs & drug costs). A range of cost estimates obtained from NHS laboratories was
used in a two-way sensitivity analysis.
In the longer term, some costs will be reduced because ACE inhibitor/ARB therapy
slows progression of disease
Also, in the longer term, some costs will be increased because patients survive for
longer with ACE inhibitor/ARB therapy
Disease prevalence
The prevalence of renal insufficiency (GFR estimated from serum creatinine) and proteinuria/
macroalbuminuria (from a random ACR) was determined in different age categories in various
adult screening groups in the cross-sectional NHANES III study.360 A total of 14,622 adults that
represented the American non-institutionalised population were included in this study.
13
Table C.1 NHANES III360 prevalence of CKD stages 35 (GFR <60 ml/min/1.73 m2) by age
Age
2039
4.4%
2.1%
4059
6.7%
4.3%
6079
19.6%
9.1%
80+
31.5%
21.5%
Table C.2 NHANES III360 prevalence of macroalbuminuria (ACR >48 mg/mmol) by age
People who do not have diabetes but
do have hypertension
Age
GFR< 60 ml/min/1.73m2
GFR 60
GFR<60
GFR 60
2039
12.8%
0.5%
0.4%
0.2%
4059
7.0%
1.3%
0.1%
0.2%
6079
4.7%
1.0%
0.2%
0.9%
80+
6.7%
3.8%
3.0%
0. 1%
The prevalence of cases, those that will be treated with high dose ACEI/ARB therapy after
diagnosis, is calculated as the prevalence of GFR <60 ml/min/1.73 m2 multiplied by the prevalence
of macroalbuminuria. So for example:
G
In people with hypertension aged 60, the prevalence of cases is 19.6% x 4.7% = 0.921%
G
In people who do not have hypertension, aged 60, the prevalence of cases is 9.1% x 0.2%
= 0.018%
Diagnostic accuracy
Estimates regarding the sensitivity and specificity of the reagent strip test and ACR were decided
upon following consideration of previous models, the CKD guideline reviews of clinical
evidence and GDG member expert opinion.
For the purposes of the model, the GFR estimation is assumed to be 100% sensitive and
specific. The sensitivity and specificity of ACR was also assumed to be 100% in the base case
analysis. For both GFR and ACR, a second test was costed following an initial positive test.
The sensitivity (92%) and specificity (62%) of the reagent strip test were averages from the two
studies83,84 in the clinical review that measured sensitivity and specificity with a cut-off of
0.3 g/l (equivalent to 0.5 g/day), the threshold that was identified as most clinically relevant by
the GDG.
14
Progression to ESRD
To estimate progression to ESRD we followed the method of one of the previously published
models,157 using the following data:
G
Annual rate of progression in patients with no diabetes, no hypertension and no
proteinuria, from the Okinawa screening study361 with a sample of 2485 and 7 years,
9 months of follow up = 0.004061 = ln(1(77/2485))/7.75
G
Probability of progression in first 12 months in patients with no diabetes, no
hypertension and no proteinuria, calculated from the annual rate above = 0.004053 =
1exp(0.004061)
G
Relative risk of progression: proteinuria vs no proteinuria = 3.858 (sourced from the
Okinawa screening study361)
G
Relative risk of progression: hypertension vs normotension in people with proteinuria
= 2.08 (sourced from Jafar et al.s 2003 meta-analysis227)
G
Relative risk of progression: ACE inhibitors vs no ACE inhibitors = 0.69 (sourced from
Jafar et al.s 2001 meta-analysis239)
We used the following annual transition probabilities in the model:
G
Hypertension and proteinuria untreated (Z) = b*c*d = 0.033
G
Hypertension and proteinuria treated (Y) = Z*e = 0.022
G
Normotension and proteinuria untreated (X) = b*c = 0.016
G
Normotension and proteinuria treated (W) = X*e = 0.011
For the tested true positive participants, a 31% reduction in progression from stage 3A/3B/4 to
stage 5 was assumed. This was based on a relative risk of 0.69 reported by Jafar et al. 2001, a
meta-analysis on 1860 non-diabetic patients who were mainly hypertensive.
15
Mortality
Table C.3 Hazard ratio for death according to CKD stage and age (OHare et al.136)
Age
CKD stage 5
1844
2.14
5.86
4554
1.83
4.47
5564
1.64
4.29
6574
1.32
3.82
7584
1.22
3.68
85+
1.14
3.6
All cause mortality rates were calculated using the hazard ratio for death for CKD patients
stratified by age and GFR.136 To get the age-specific death rates for the model, these ratios were
multiplied with the age-specific death rates for the general population in England and Wales.363
For the true positives, the mortality rate was reduced by 22%, attributable to ACE inhibitor/
ARB therapy.
Costs
Direct costs of medical care related to CKD and hypertension were included. All costs were in
20067 UK pounds sterling. The costs of testing incorporated initial GFR estimation, reagent
strip testing and/or ACR estimation and GP practice nurse time costs (see Table C.4).
It was assumed that following a GFR test result, high-risk individuals would be requested to
visit the GP surgery to provide a urine sample for urinalysis. They may be attended to by either
the practice nurse or health care assistant. Therefore a single visit to a GP practice nurse is
accounted for in testing strategies 3 and 4. In strategy 2, a second visit is costed if the first
urinalysis is negative. Following the review and recording of results, action may involve no
further assessment or may contribute to a follow-up appointment with GP or practice nurse or
a referral to specialist care.
16
Reference
Haematology
2.78
Biochemistry
2.03
3.10*
Brighton Laboratory
Phlebotomy
2.96
0.21/strip
PTH assay
15.00
15.00
25.00
PSSRU 2006
PSSRU 2006
Ultrasound
75.14
242.47
135.84
8.00
Drug costs
Costs of antihypertensive drug therapy were based on prices quoted in the British National
Formulary.344 The baseline drug regimen adopted for hypertensive patients was a calcium
channel blocker and thiazide diuretic. These drugs are the most widely prescribed for
hypertension.366
Drug
Dose/schedule
Proportion of
patients
(a)
Bendroflumethiazide
2.5 mg od
100%
1.43
18.64
18.64
Amlodipine
10 mg qd
100%
3.08
40.15
40.15
Cost/year
(c = 13.04*b)
58.79
The costs of full-dose ACE inhibitor/ARB therapy for CKD treatment in people with
hypertension and people with neither diabetes nor hypertension are represented in Tables C.6
and C.7. The drug costs are different for those with neither diabetes nor hypertension,
inasmuch as there are no drug costs for hypertension other than ACE inhibitor/ARB therapy
for the true positives.
17
Drug
Dose/schedule
Proportion of
patients
(a)
Bendroflumethiazide
2.5 mg od
100%
1.43
18.64
18.64
Amlodipine
10 mg qd
100%
3.08
40.15
40.15
Ramipril
10 mg
94%*
3.16
41.19
38.72
Irbesartan
300 mg od
6%*
16.91
220.43
13.23
Cost/year
(c = 13.04*b)
110.74
Drug
Dose/schedule
Proportion of
patients
(a)
Ramipril
10 mg
94%*
3.16
41.19
38.72
Irbesartan
300 mg od
6%*
16.91
220.43
13.23
Cost/year
(c = 13.04 x b)
51.95
GP care costs
The number of visits per year was determined by whether they or not they are diagnosed with
hypertension or CKD (Table C.8). People were assumed to have pathology tests at 7.78 per
year365 regardless of whether or not they are diagnosed with hypertension.
Table C.8 General practitioner care costs
GP visits per
patient per year*
GP visit costs ()
per patient per year
150
100
100
50
* The number of GP visits per year made by people with hypertension and CKD, was sourced from the Australian CKD
model.157 For the people without hypertension, the number of visits was assumed.
** The cost of a GP visit was 25.364
18
CKD stage 34
CKD stage 5
185.52
756.23
415.41
438.63
1.8
CKD stage 5
3.1
Mean admissions per year
Age 1544
Age 4564
Age 6574
Age 75+
General Population
0.20
0.24
0.45
0.75
CKD stage 34
0.36
0.44
0.83
1.35
CKD stage 5
0.63
0.75
1.42
2.33
Age 4564
Age 6574
Age 75+
CKD stage 34
340
408
1,339
2,193
CKD stage 5
587
703
2,306
3,776
19
A general hospital admission rate was calculated for England and Wales, and combined with the
hazard ratio for any hospital admission according to CKD stage (from Go et al.13) produced an
admission rate by CKD stage. Using reference costs for general renal disorder admissions that
were differentiated by age, the cost of inpatient admissions according to age and stage were
calculated.
Haemodialysis
(HD) main unit
Haemodialysis
(HD) satellite unit
Automated
Peritoneal Dialysis
(APD)
Continuous perambulatory
Peritoneal Dialysis
(CPD)
Cost
Cost
Cost
Cost
Direct nursing
7,969
7,071
371
357
2,132
1,905
1,995
1,995
10,952
10,952
14,152
9,772
1,117
1,026
901
901
Dialysis machines
720
720
924
Machine maintenance
766
583
766
Anaemia therapy
3,740
3,328
2,140
2,140
Hospital transport
2,438
1,905
114
114
Overheads
5,188
5,179
290
290
Total cost
35,022
32,669
21,655
15,570
Disposables
Medical supervision
33,845
18,613
Proportion on HD/PD
76%
21%
Utilities
A Utility score of 0.734 was used for CKD stages 3 and 4. It was sourced from the Australian
model.157 This score captures the utility for hypertensive patients on therapy. The Australian
model used utility-based quality of life scores derived from data collected in the Australian
Diabetes and Lifestyle study (Ausdiab).141 A cross-sectional study of 11,246 non-institutionalised
Australians aged 25 years or older.
20
A Utility score of 0.603 was used for patients in CKD stage 5 and on RRT (de Wit et al.372). This
study assessed the health-related quality of life (HRQOL) of 135 haemodialysis and peritoneal
dialysis patients.
Reagent 1
Reagent 2
ACR
15.44
18.22
18.44
18.46
2.14
1.83
1.81
1.81
2.01
1.63
1.60
1.60
19.59
21.68
21.85
21.86
0%
0.848%
0.915%
0.921%
The costs of testing were highest in the reagent 2 strategy as were overall costs. The costs of
RRT were highest in the no testing strategy.
For the hypertensive population, the base case analysis, the key result is that testing is costeffective for all ages and that ACR after GFR is the most cost-effective strategy (Table C.13 and
Table C.14). The incremental cost-effectiveness thresholds were below 20,000 per QALY
gained. The ACR strategy dominates the reagent 2 strategy: that is, the ACR strategy is
cheaper and more effective.
21
Table C.13 Model 1 base case resuts (women aged 60 with hypertension but not diabetes)
Strategy
Cost
Effectiveness
No testing
506.7
0.0923 QALY
Reagent 1
516.7
0.0996 QALY
1,362/QALY
ACR
517.8
0.1005 QALY
1,327/QALY
Reagent 2
521.9
0.1004 QALY
(Dominated)
506.7
0.0923 QALY
ACR
517.8
0.1005 QALY
1,358/QALYs
Table C.14 Model 1 base case resuts: cost-effectiveness by age and sex
Men
Women
Age 20
Age 40
Age 60
Age 80
22
3.00
GFR + ACR
2.70
GFR + PCR
2.40
2.10
1.80
1.50
1.20
0.90
0.60
0.30
0.00
0.960
0.969
0.978
0.987
0.996
Sensitivity of PCR
NB: sensitivity of ACR=100%.
No testing, GFR + 2 reagent strips, GFR + 1 reagent strip do not appear in the graph as they were not cost-effective.
Figure C.6
Progression rates
Even at a 0.01% rate of progression to ESRD, the ACR strategys ICER was still only 12,000/
QALY compared to the no testing strategy.
If we assume that every patient who progresses to ESRD is automatically placed on RRT, the
ACR strategy still proves the most cost-effective.
Effectiveness of treatment
When the treatment effect of ACE inhibitor/ARB therapy on progression is varied while
keeping the treatment effect on mortality constant (RR=0.78), the results are insensitive. Even
with no effect of ACE inhibitor / ARB therapy on progression, the ACR strategy is marginally
cost-effective at 22,000 per QALY gained.
If we assume no treatment effect on mortality (applying a mortality rate of an untreated CKD
population), then if the relative risk reduction on progression is decreased below 11%, the ACR
strategy ceases to be cost-effective.
23
When the treatment effect on mortality is varied between 0 and 100% reduction, while keeping
the treatment effect on progression to ESRD constant (RR=0.69) the ACR strategy is most
cost-effective throughout.
Cost of RRT
The annual cost of renal replacement therapy was varied between 5000 and 100,000. At an
annual cost as low as 5000 for RRT, the ACR strategy remained cost effective at 9000 per
additional QALY gained. At the other extreme, at an annual cost of 100,000 the ACR strategy
dominated the other strategies.
Cost of drugs
If all patients with CKD were placed on the more expensive drug (high dose ARB instead of
high dose ACE inhibitor), the ACR strategy is still the most cost effective with an ICER of
4,000 per QALY gained.
RRT mortality
The mortality rate while on RRT was also explored. The model proved to be insensitive to
changes in this rate. At a mortality hazard ratio of 5 the ACR strategy has an ICER of
6000/QALY.
women): all three testing strategies cost more than 400 000 per QALY gained (Table C16).
Indeed testing was not cost-effective for any age group except age 80 where the prevalence was
highest and reduction in mortality greatest (Table C.17).
Table C.15 Base case results (women aged 55 with neither diabetes nor hypertension):
health outcomes per patient tested
Mean
No testing
Reagent 1
Reagent 2
ACR
21.41
24.25
24.48
24.50
1.50
1.24
1.22
1.22
1.69
1.33
1.30
1.29
24.60
26.82
27.00
27.01
0.0000%
0.0040%
0.0043%
0.0043%
Life-years
Cases found
Table C.16 Model 2 base case resuts: cost per QALY gained
Strategy
Cost
Effectiveness
No testing strategy
1.9
0.00050 QALY
Reagent 1 strategy
16.9
0.00053 QALY
489,899/QALY
ACR strategy
18.3
0.00054 QALY
411,726/QALY
Reagent 2 strategy
21.8
0.00054 QALY
(Dominated)
All strategies
1.9
0.00050 QALY
18.3
0.00054 QALY
482,082 /QALY
Table C.17 Model 2 base case resuts: cost-effective strategy by age and sex
Men
Women
Age 20
Age 40
Age 55
Age 65
Age 70
Age 75
Age 80
25
C.5 Discussion
C.5.1 Summary
s
C.5.2 Limitations
s
26
but we believe this number would be small compared to the number of crash landers that are
diagnosed at the RRT stage.
Compliance with medication might be less than that observed in trials and therefore
effectiveness might be over-estimated but this is difficult to quantify.
In the base case analysis, ACR is assumed to be 100% sensitive and 100% specific. The results
were not sensitive to the sensitivity of ACR. However, even in the sensitivity analysis, the model
does not measure the health impact or long-term costs of false positives. We believe these to be
very small effects as a consequence of repeat testing after a positive test result.
In the base case analysis we include the costs and health effects of ACE inhibitor/ARB treatment
for all patients. We acknowledge that a large proportion of patients may be on low dose ACE
inhibitor. The cost-effectiveness for this group is difficult to quantify but may not be very
different from other patients. This is because, although such patients are likely to get less health
gain from treatment they are also likely to incur less incremental cost.
C.6 Conclusion
The model suggests that case-finding among high-risk groups is cost-effective. Use of
albumin:creatinine ratio, without prior reagent strip, appears to be the most cost-effective
option.
27
Personal pecuniary
interest
Personal family
interest
Non-personal
pecuniary interest
BAKHSHI Lina
None
None
None
None
BENETT Ivan
None
None
CROWE Emily
None
None
None
None
DODWELL Miranda
None
None
None
None
DUNN Robert
None
None
National Advocacy
Officer
National Kidney
Federation
None
FORREST Caroline
None
None
None
None
None
None
None
HALPIN David
None
My department has
None
undertaken
commercial research
trials for GSK, Astra
Zeneca, Boehringer
Ingelheim, SR
Pharma, Almirall and
Novartis
HARRIS Kevin
Member of Baxter
Medical Advisory Board
2006/7 (non-specific)
Member of Genzyme
Medical Advisory Board
2006/7 (non-specific)
Member of Shire Medical
Advisory Board 2006
(non-specific)
Member of Novartis
Medical Advisory Board
2006 (non-specific)
Lecture for BMS/Sanofi,
Pfizer, GSK, Boehringer
Ingelheim on CKD
(non-specific)
None
Departmental
funding for bone
management nurse
(Genzyme)
Unrestricted
educational grant
from Fresenuis
Support for clinical
fellowship from Baxter
Support for part
time clerical post
from Amgen
Departmental
reimbursement for
my time to be a
member of the
Optimal CKD
Management
Programme Board
(ended September
2006)
continued
28
Personal pecuniary
interest
Personal family
interest
Non-personal
pecuniary interest
JOHN Ian
None
None
None
None
LAMB Edmund
None
None
None
None
MCINTRYE Natasha
None
None
None
OMARJEE Suffiya
None
A family member
conducts drug trial
research for several drug
companies in the field of
gastroenterology in South
Africa.
None
None
ORIORDAN Shelagh
None
None
None
None
RODERICK Paul
None
STEPHENS David
None
None
None
STEVENS Paul
Roche UK research
grant for developing
an expert system for
the management of
chronic kidney
disease
None
SUTTON Jaim
None
None
None
None
TOK Meiyin
None
None
None
None
None
29